Physiol Rev 86: 245–278, 2006;
doi:10.1152/physrev.00010.2005.
Respiratory Tract Mucin Genes and Mucin Glycoproteins
in Health and Disease
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
Research Center for Genetic Medicine, Children’s National Medical Center and Departments of Pediatrics and
of Biochemistry and Molecular Biology, George Washington University, Washington, District of Columbia;
and Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
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I. Introduction
A. Overview
B. Mucin glycoproteins
C. Molecular tools for MUC identification
D. Mucin expression in epithelial tissues/cells and airway cells
E. Mucins in airway secretions/lung mucus
F. Comparative biology of mucin gene expression in the respiratory tract
II. Mucin Overproduction in Chronic Airway Diseases
A. Overview
B. Mucin overproduction in asthma
C. Mucin overproduction in COPD
D. Mucin overproduction in CF
III. Regulation of Mucin Genes
A. Overview
B. Transcriptional regulation by infectious mediators of mucin genes
C. Transcriptional regulation by inflammatory/immune response mediators
D. Posttranscriptional regulation of mucin genes
IV. Summary and Future Directions
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Rose, Mary Callaghan, and Judith A. Voynow. Respiratory Tract Mucin Genes and Mucin Glycoproteins in Health
and Disease. Physiol Rev 86: 245–278, 2006; doi:10.1152/physrev.00010.2005.—This review focuses on the role and
regulation of mucin glycoproteins (mucins) in airway health and disease. Mucins are highly glycosylated macromolecules (ⱖ50% carbohydrate, wt/wt). MUC protein backbones are characterized by numerous tandem repeats that
contain proline and are high in serine and/or threonine residues, the sites of O-glycosylation. Secretory and
membrane-tethered mucins contribute to mucociliary defense, an innate immune defense system that protects the
airways against pathogens and environmental toxins. Inflammatory/immune response mediators and the overproduction of mucus characterize chronic airway diseases: asthma, chronic obstructive pulmonary diseases (COPD), or
cystic fibrosis (CF). Specific inflammatory/immune response mediators can activate mucin gene regulation and
airway remodeling, including goblet cell hyperplasia (GCH). These processes sustain airway mucin overproduction
and contribute to airway obstruction by mucus and therefore to the high morbidity and mortality associated with
these diseases. Importantly, mucin overproduction and GCH, although linked, are not synonymous and may follow
from different signaling and gene regulatory pathways. In section I, structure, expression, and localization of the 18
human MUC genes and MUC gene products having tandem repeat domains and the specificity and application of
MUC-specific antibodies that identify mucin gene products in airway tissues, cells, and secretions are overviewed.
Mucin overproduction in chronic airway diseases and secretory cell metaplasia in animal model systems are
reviewed in section II and addressed in disease-specific subsections on asthma, COPD, and CF. Information on
regulation of mucin genes by inflammatory/immune response mediators is summarized in section III. In section IV,
deficiencies in understanding the functional roles of mucins at the molecular level are identified as areas for further
investigations that will impact on airway health and disease. The underlying premise is that understanding the
pathways and processes that lead to mucus overproduction in specific airway diseases will allow circumvention or
amelioration of these processes.
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0031-9333/06 $18.00 Copyright © 2006 the American Physiological Society
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MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
I. INTRODUCTION
A. Overview
The apical epithelial surfaces of mammalian respiratory, gastrointestinal, and reproductive tracts are coated
by mucus, a mixture of water, ions, glycoproteins, proteins, and lipids. Mucosal components are secreted apically by goblet cells in polarized epithelium and by secretory cells in the submucosal glands (SMG). Mucus provides a protective barrier against pathogens and toxins
and contributes to the innate defensive system in mucosal
immunology (54).
Mucin glycoproteins (mucins) are the major macromolecular constituents of epithelial mucus and have long
been implicated in health and disease. Mucins historically
are large, highly glycosylated, viscoelastic macromolecules that are difficult to isolate and purify (218). The
application of recombinant DNA technology to the mucin
field resulted in the cloning of MUC genes that encode
mucin protein backbones.1 This enlarged the definition of
mucins to include membrane-tethered, as well as se1
Abbreviations for human mucin genes and gene products follow
the conventions in the Unigene database where human genes are capitalized and italicized, gene products are capitalized but not italicized,
and numbers are not prefaced by a dash or space.
Physiol Rev • VOL
creted, mucins. The development of molecular tools to
identify mucins by their MUC protein backbone enabled
studies on the expression and localization of MUC gene
products in tissues, cells, and secretions. Currently, investigations on specific mucins and their roles in diseases,
mucosal defense, and epithelial repair/remodeling are underway in many laboratories. Mucins implicated in cancer
(110), lung diseases (153, 286), gastrointestinal diseases
(53, 70), as well as mucins expressed in the eye (90) and
ear (164), have recently been reviewed.
This review focuses on mucins in airway health and
disease, which are expressed in the conducting airways
(trachea, bronchi, bronchioles) of the lower respiratory
tract. Airway mucins are major components of the soluble
layer and/or viscoelastic gel that comprise lung mucus in
healthy airways and contribute to the mucociliary defense
system that protects the lungs against pathogens and
environmental toxins (219). Mucin production entails several biological processes (Fig. 1), as the biosynthesis of
even the simplest mature glycosylated mucin requires
transcription of a MUC gene to encode a MUC mRNA,
which is then translated into a MUC protein backbone
that is posttranslationally modified by one or several glycosyltransferases (GT). Secretory mucins are stored in
secretory granules and released at the apical surface in
response to mucin secretagogues, while membrane-tethered mucins are integrated into the cell membrane.
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FIG. 1. Model of biosynthesis and
secretion of mucin glycoproteins in a
goblet or mucus cell. Activated transcription factors upregulate expression of
MUC genes in the nucleus. New MUC
transcripts are translated to MUC proteins on ribosomes (F) and cotranslationally inserted into the endoplasmic reticulum (ER). O-glycosylation of the MUC
protein backbone is initiated posttranslationally in the cis-Golgi following transfer of GalNAc to serine or threonine
amino acids by an N-acetylgalactosaminyl peptidyltransferase. The addition of
GalNAc likely alters the conformation of
globular apomucins to a more linear molecule (228), which facilitates transfer of
subsequent hexoses and/or hexosamines
to each nascent O-glycan in a stepwise
manner by a series of glycosyltransferases (GT). Mature, e.g., fully glycosylated, mucins are packaged and stored in
secretory granules until a mucin secretagogue triggers mucin secretion at the apical surface.
MUCIN GENES AND GLYCOPROTEINS
247
FIG. 2. Schematic drawing of a secretory mucin glycoprotein depicting a MUC protein backbone and its O-glycans. A MUC protein backbone
typically consists of an NH2-terminal domain (blue), one or more central domain(s) with a high number of tandem repeat (TR) domains (yellow),
and a COOH-terminal domain (green). Numerous O-glycans are attached to threonine (F) or serine (E) residues in the TR domains. O-glycans exhibit
size heterogeneity, which may reflect incomplete biosynthesis during elongation and termination of O-glycans or differences in substrate preferences
of various GTs at specific serine or threonine sites.
Physiol Rev • VOL
carried out in airway epithelial cancer cell lines and/or
primary normal human bronchial epithelial (NHBE) cells.
When grown on an extracellular matrix and maintained at
an air-liquid interface (ALI), NHBE cells differentiate to
morphologically mimic conducting airway epithelium (reviewed in Refs. 2, 305), thus providing a useful model
system for airway studies. A brief summary and overview
of future directions for research in lung mucin biology are
provided in section IV.
B. Mucin Glycoproteins
1. Mucin classification
Mucins are complex glycoproteins synthesized in epithelial cells and typically characterized by large molecular weight (2–20 ⫻ 105 Da), high carbohydrate content
(50 –90% by weight) reflecting a large number of O-glycans, and an extensive number of tandem repeats (TR) in
the protein backbone (Fig. 2). The TR domains are the
characteristic feature that distinguishes mucins from
other glycoproteins, especially from membrane-bound
glycoproteins/receptors that have extracellular regions
high in serine, threonine, and proline and may be members of the immunoglobulin superfamily. Mucins are classified by their MUC protein backbone, which is encoded
by a MUC gene. MUC genes are localized to chromosomes
1, 3, 4, 7, 11, 12, and 19 (Table 1). MUC gene products vary
in size. MUC transcripts range from 1.1 to ⬎15 kb, while
MUC proteins, which account for 10 –50% (wt/wt) of mucin mass, have 377 to ⱖ11,000 amino acids in their protein
backbones.
More than 20 human and murine mucin genes are
deposited in GenBank. However, human MUC and rodent
Muc genes are not always distinguished and the question
of whether a macromolecule requires TR or only a significant amount of O-glycosylation sites for classification as
a mucin needs to be resolved. For example, Muc10 is a
murine gene and the ortholog of the human MUC7 gene
(62), while Muc14 is a murine gene and the homolog of a
gene that encodes human endomucin-1/2 (131).
Additionally, the definition of what determines a mucin gene is not always consistent. Perhaps serine/threonine/proline-rich TR domains (see sect. IB2) should define
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Mucus and mucins are overproduced in the airways
of patients with chronic airway diseases, which greatly
contributes to airway obstruction in patients with asthma,
chronic obstructive pulmonary diseases (COPD), or cystic fibrosis (CF) (21, 123, 216, 224, 283). These diseases
are characterized by inflammatory/immune response mediators, which are released into airway tissue and airway
fluid/secretions. Some mediators can regulate MUC gene
expression and/or stability, as well as mucin secretion (2,
47). However, the mechanisms that regulate mucin secretion are independent of the signal transduction mechanisms that lead to upregulation of MUC gene expression
and thus increased mucin biosynthesis, and this has been
well and succinctly overviewed (2). Mucin secretion in
vivo is typically initiated by a secretagogue and is rapid,
occurring within seconds to minutes (58, 282), in contrast
to MUC gene regulation, which requires minutes to hours
(155), and mucin biosynthesis, which requires 6 –24 h
(185). The term mucin hypersecretion is sometimes used
to encompass all the processes that contribute to mucin
overproduction in chronic airway diseases, rather than to
describe a secretagogue-initiated secretory response. An
increased understanding of the molecular mechanisms
that regulate mucin secretion is evolving (159). However,
secretion/hypersecretion is not covered herein; readers
are referred to recent reviews on this topic (58, 129).
In section I, current information on the structure and
properties of mucins, especially those expressed in the
lower respiratory tract, as well as molecular tools used to
identify MUC gene products in tissues, cells, and secretions, is presented. Information on mucin overproduction
in chronic airway diseases is overviewed in section II and
then addressed in disease-specific subsections on asthma,
chronic bronchitis, and CF. Upregulation of MUC genes
and goblet cell hyperplasia (GCH) are fundamental processes that contribute to and sustain mucin overproduction in the airways of patients with chronic lung diseases.
Information on GCH and secretory cell metaplasia in
animal models of airway diseases is integrated into each
disease-specific subsection in section II, together with
pertinent information on mucin gene regulation. However, the rapid increase in information on this latter topic
warranted a separate section on “regulation of mucin
genes” in section III. These studies have typically been
248
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
1. Chromosomal localization of human
mucin genes
TABLE
MUC Gene
Reference Nos.
1q21–q24
1q21
1p13
3q13.3
3q29
3q29
4q13.3
7q22
7q22
7q22
7q22
7q22
11p15.5
11p15.5
11p15.5
11p15.5
11p14.3
11q23.3
12q12
12q24.3
19q13.2
19q13.2?
264
180
150
302
208
108
23
82,100
209
301
301
101
93,204
179,187,204
69,204
204,276
197
142
46
242
307
192
MUC1
MUC9
MUC13
MUC4
MUC20
MUC7
MUC3A
MUC3B
MUC11
MUC12
MUC17
MUC2
MUC5AC
MUC5B
MUC6
MUC15
MUC18
MUC19
MUC8
MUC16
The chromosomal localization of genes listed as mucin genes in
GenBank but which lack tandem repeats, e.g., MUC15 and MUC18, are
included.
a mucin, while a significant amount of serines, threonines,
and a large number of O-glycosides would define a mucinlike glycoprotein. Three of the mucin genes in GenBank encode numerous serine and threonine residues,
but do not encode TR domains in their protein backbones
(Tables 2 and 3). These are MUC14, a membrane-bound
O-sialoglycoprotein (131), MUC15, a membrane-tethered
glycoprotein (197), and MUC18/CD146, a neural cell adhesion member of the immunoglobulin superfamily (151).
If these three macromolecules are considered as serine/
threonine-rich glycoproteins rather than mucins, then the
present list of human mucins would have 18 members all
of which had TR, e.g., MUC1, MUC2, MUC3A, MUC3B,
MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, MUC9,
MUC11, MUC12, MUC13, MUC16, MUC17, MUC19, and
MUC20. Clarification of what constitutes a MUC gene
product is evolving and should eventually be standardized. This process will be facilitated by the establishment
of a mucin website (www.mucin.org), initiated by Dr. Yin
TABLE
2.
2. MUC protein backbones: TRs
Eighteen of the ⬎20 mucin genes that are deposited
in GenBank encode TRs, the exceptions being MUC14,
MUC15, and MUC18 (see above and Tables 2 and 3). The
tandem repeating nucleotide sequences are typically encoded by a single central exon in a MUC gene. Many MUC
genes are polymorphic, with alleles having a variable
number of TRs (VNTR) (81), as indicated in Table 3.
Additional variations occur with minor changes in the
length of the repeat unit (length polymorphisms) and
repeating sequence (sequence polymorphisms). Thus different individuals can express different forms of the same
MUC gene product. In addition, MUC genes may undergo
alternative splicing (183). Changes in VNTR are reported
in cancer (reviewed in Ref. 110), ulcerative colitis (143),
and respiratory diseases (124).
Classification of human mucins by MUC protein backbone structures
Classification
Mucins
Membrane-tethered with TR
Secreted, cysteine-rich with TR
Secreted, cysteine-poor with TR
Mucins without TR
MUC1, MUC3A, MUC3B, MUC4, MUC11, MUC12, MUC13, MUC16, MUC17, MUC20
MUC6, MUC2, MUC5AC, MUC5B, MUC19
MUC7, MUC8, MUC9
MUC14, MUC15, MUC18
Classification of human mucins is as listed in GenBank. TR, tandem repeat.
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Chromosome Locus
Chen while in Dr. Reen Wu’s group at the University of
California, Davis.
In addition to TR (see sect. IB2), additional modular
motifs are present in the amino and carboxy termini of
MUC protein backbones. These allowed classification as
membrane-tethered or secretory mucins, with secretory
mucins being further subdivided into those that are cysteine rich or cysteine poor (Table 2). MUC1, MUC4,
MUC3A, MUC3B, MUC12, MUC13, MUC15, MUC16,
MUC17, MUC18, and MUC20 mucins have transmembrane domains in their carboxy terminus and thus are
type 1 membrane proteins. MUC2, MUC5AC, MUC5B, and
MUC6 are large secretory mucins with cysteine-rich motifs. MUC19 is a secretory cysteine-rich mucin recently
identified by in silico cloning and subsequently characterized (46). MUC7 is a small, secreted mucin that lacks
cysteine-rich domains. MUC8 is a large, secreted mucin
that lacks the von Willebrand factor (VWF) D4 or C1, C2
domains typically present in the carboxy end of large
secretory mucins. Descriptions of modular motifs, as well
as models of most of the identified MUC proteins, are
detailed in two recent reviews (60, 110), to which readers
are referred. Depictions of specific membrane-tethered
mucins (MUC1 and MUC4), secretory cysteine-rich mucins (MUC2, MUC5AC, and MUC5B), and the secreted
non-cysteine-rich mucin MUC7 are shown in Figure 3.
MUCIN GENES AND GLYCOPROTEINS
249
TRs are unique in sequence and size (Table 3) and
thus are the defining characteristic of each MUC protein.
Among different mucins, TRs vary in length (5–375 amino
acids) and in number (5–395 repeats). Some MUC proteins have two domains with different TR sequences, e.g.,
MUC2, MUC3A, MUC3B, and MUC5AC. The two major
airway mucins, MUC5AC and MUC5B, have TR domains
that are repeated four or five times in their protein backbones, respectively, and are separated by cysteine-rich
domains (Fig. 3). Each TR contains proline and is rich in
serine and/or threonine residues, the sites of O-glycosylation. Thus TRs largely determine a mucin’s degree of
glycosylation, as longer or more highly repeated TR sequences can allow for hundreds of O-glycans per molecule (Figs. 2 and 3). MUC5B, for example, contains a
repeat of 29 amino acids with a total of 16 serines and
threonines. Seventy-two repetitions of the 29 amino acid
sequence contribute 1,152 possible O-glycosylation sites
to the MUC5B backbone. The number of TRs in a MUC
protein also determines mucin size as they elongate the
protein backbone and thus increase mucin molecular
mass. They also likely contribute to the structural and
functional diversity of mucins in ways that are not yet
appreciated at the molecular or physiological level. For
example, the TR domains of MUC2 are uninterrupted by
cysteine-rich domains, in contrast to MUC5AC and
MUC5B (Fig. 3). This perhaps reflects the need for
MUC5AC/B to couple to the mucociliary escalator in the
airways, whereas MUC2 may need to be more rigid to
better protect the intestinal epithelium against proteolytic
attack. Indeed, MUC2 is considered an insoluble mucin
biochemically (10).
TRs are the primary domains to which O-glycans are
attached, and O-glycans can alter mucin conformation.
This has been shown for ovine submaxillary mucin, which
Physiol Rev • VOL
undergoes a change from an extended filament to a globular form following enzymatic removal of the disaccharide O-glycans (228). Airway mucins typically present as
flexible filamentous structures (227, 247), which on aggregation form a large interwoven network (227) quite different from the massive ropelike structures characteristic
of sheep submaxillary mucin aggregates (50). Thus TR
and their attached O-glycans influence the size, shape, and
mass of mucins, thereby contributing to the biophysical
and biological properties of mucus itself. For example,
larger, bulkier, heavier mucins might result in more viscous mucus. Future studies should reveal the molecular
details wherein MUC-specific TR contribute to the biochemical and physical properties of mucins.
TR domains are typically not conserved between human MUC and rodent Muc genes, whereas the non-TR
motifs at the amino- and carboxy-terminal domains of
many mucins are typically highly conserved between species, as first shown for MUC1/Muc1 (259).
3. Mucin glycosylation
Like mucins, many macromolecules, including cell
adhesion markers and selectin ligands, have O-glycans
attached to serine or threonine residues in their protein
backbone (60, 219). However, mucins are 50 –90% carbohydrate by mass and have numerous (dozens to several
hundred) O-glycosylation sites per molecule due to the
high number of TR in each MUC protein backbone (Table
3). Studies to determine and/or predict which serines or
threonines in TRs or in mucins are O-glycosylated are
challenging (88).
O-glycosylation is a major part of mucin biosynthesis
and requires an N-acetylgalactosaminyl peptidyltransferase and one or more GTs depending on the final O-
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FIG. 3. Modular motifs in MUC proteins of some airway mucins. A: membranetethered mucins MUC1 and MUC4. B: secretory cysteine-poor mucin MUC7. C: secretory cysteine-rich mucins MUC2,
MUC5B, and MUC5AC. The number of TR
in a given region is expressed as n below
each MUC. Note that the relative scale for
MUC7 is twice that of the other mucins.
Readers are referred to Refs. 110 or 60 for
more details on specific motifs in the NH2or COOH-terminal domains, respectively.
AMOP, adhesion associated extracellular
domain; EGF, epidermal growth factor-like
domains; nidogen-like domain, an extracellular domain in nidogen, a sulfated glycoprotein which binds to collagen IV and is
tightly associated with laminin (72); PTS,
proline, threonine, serine-rich domains;
SEA, extracellular domain associated with
O-glycosylation; vWF-D and C-like domains
are present in the von Willebrand factor
glycoprotein (232). [Models adapted primarily from Dekker et al. (60).]
250
TABLE
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
3.
Tandem repeat (TR) sequences of MUC proteins
Amino
Acids/TR
Repeating Sequence
MUC1
20
GSTAPPAHGVTSAPDTRPAP
MUC2
23
16
PTTTPITTTTTVTPTPTPTGTQT
PPTTTPSPPPTSTTTL
17
375
MUC3B
17
375
16
8
5
MUC4
MUC5AC†
MUC5B†
MUC6
29
169
MUC7
MUC8
23
13
41
MUC9
MUC11
MUC12
MUC13
MUC14
MUC15
MUC16
15
28
28
15
0
0
156
MUC17
59
MUC18
MUC19
0
7
7
15
16
9
8
5
19
MUC20
Number of TR/MUC*
Reference Nos.
83,84
21-125; 41 and 85 are
most common
21
51-115; 100-115 are
most common
20
Unknown
84
99
275
ITTTETTSHSTPSFTSS
TTTPNTTSHSTPSFTSSTIYSTVSTSTTAISSAS
PTSGTMVTSTTMTPSSLSTDTPSTTPTTITYPS
VGSTGFLTTATDLTSTFTVSSSSAMSKSVIPSS
PSIQNTETSSLVSMTSATTPSLRPTITSTDSTLT
SSLLTTFPSTYSFSSSMSASSAGTTHTETISSLP
ASTNTIHTTAESALAPTTTTSFTTSPTMEPPSTT
VATTGTGQTTFPSSTATFLETTTLTPTTDFSTE
SLTTAMTSTPPITSSITPTDTMTSMRTTTSWPT
ATNTLSPLTSSILSSTPVPSTEVTTSHTTNTNPV
STLVTTLPITITRSTLTSETAYPSSPTSTVTESTT
EITYPTTMTETSSPATSLPPTSSLVSTAETAKTP
TTNL
ITTTETTSHSTPSFTSS
Same sequence as for MUC3A
ATPLPVTDTSSASTGH
TTSTTSAP
TTVGP/S
ATGSTATPSSTPGTTHTPPVLTTTATTPT
SPFSSTGPMTATSFQTTTTYPTPSHPQTTLPTH
VPPFSTSLVTPSTGTVITPTHAQMATSASIHSTP
TGTIPPPTTLKATGSTHTAPPMTPTTSTPVAHT
TSATSSRLPTPFTTHSPPTGS
TTAAPPTPSATTPAPPSSSAPPE
TSCPRPLQEGTRV
TSCPRPLQEGTPGSRAAHALSRRGHRVHELPT
SSPGGDTGF
GAMTMTSVGHQSMTP§
SGLSEESTTSHSSPGSTHTTLSPASTTT
SGLSQESTTFHSSPGSTETTLSPASTTT
PAPPIISTHSSSTIP
No TR
No TR
LFKSTSVGPLYSGCRLTLLRPEKHGAATGVDAI
CRLRLDPTGPGLDRERLYWELSQLTNSVTELG
PYTLDRDSLYVNGFTHRSSVPTTSIPGTSAVHL
ETSGTPASLPGHTAPGPLLVPFTLNFTITNLQY
EEDMRHPGSRKFNTTERVLQGLLKP
VSTTPVASSEASTLSTTPVDTSTPVTTSTQASS
SPTTAEGTSMPTSTPSEGSTPLTSMP
No TR
TTVAPGS
TGSKTGT
TTVAPGSFSTAATTS
SGTTVASGSSNSEATT
ATTSTDVGV
TTVASGSS
EATTS
ASSESSASSDGPHPVITESR
102,209
102
102,209
102
208
73
179
5
64
276
275
102,209
At least 33‡
Unknown
145–395
(124,17,34,66)†
209
(11,11,17,11,22)†
15–26
64
285
190
73
179
24
240
5–6
6‡
3‡
20
150
301
6
At least 36‡
At least 22‡
10
150
301
302
131
197
307
101,279
151
46
108
At
At
At
At
At
At
At
least
least
least
least
least
least
least
302
9
191,192,307
5
101
6‡
3
4
2
2
4
3
2–6
46
108
* For MUC genes that exhibit VNTR, this number is reported as a range. † The number n of TR is different in specific regions of MUC5AC and
MUC5B, as indicated in Fig. 3. ‡ The full DNA sequence for some mucins is not yet reported. The number of times a TR is present reflects data
reported by mid 2005. § Repeats are degenerate. The sequence of the first repeat is listed here.
glycan structure. O-glycosylation is initiated in the Golgi
when an N-acetylgalactosaminyl peptidyltransferase
transfers N-acetylgalactosamine (GalNAc) to a serine or
threonine when a nascent MUC polypeptide chain
traverses the Golgi, as depicted in Figure 1. Each O-glycan
Physiol Rev • VOL
is then elongated by the stepwise addition of hexoses
[galactose (Gal), N-acetylglucosamine (GlcNAc), fucose]
or sialic acid by specific GT (33, 235). More than 30 GT
have now been identified, of which at least a dozen participate in the synthesis of mucin O-glycans (34).
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MUC3A
Reference Nos.
MUCIN GENES AND GLYCOPROTEINS
251
Four major core structures (Fig. 4) have been identified in O-glycans isolated from mucins (114). The transfer of Gal to C-3 of GalNAc yields a structure that will be
core type 1 or 2. The next transferase can either add to
Gal (elongation of core 1) or to GalNAc to form a branch
(core 2). Similarly, GlcNAc can be added to GalNAc to
form core 3, which can be branched to form core 4. Core
structures can then be elongated by Gal and GlcNAc
transferases to form Gal␤1,3/4GlcNAc units, which can be
terminated by blood group determinants, sialic acid, sulfate, or fucose. Sialic acid moieties and sulfates on Gal or
GlcNAc moieties impart negative charges to mucins,
which account for their low pI values, whereas fucose
imparts hydrophobicity. Terminal sugars, because of their
hydrophobicity or charge, are thought to contribute to or
determine the physical and/or biological properties of
mucins. Thus alterations in terminal glycosylation of mucins, which may occur in disease states (see sect. IID4),
have the potential to alter the physical properties of mucins and the rheological properties of mucus.
Mucin glycosylation, like MUC gene expression, may
have restricted tissue or cell expression, and the core
structures of mucin O-glycans may be altered in disease
(219). For example, O-glycans isolated from MUC1 mucin
synthesized in vitro by breast cells from healthy women
are predominantly core type 2, while those from breast
cancer cell lines have core type 1 O-glycans (117). However, information even as to which cores are attached to
mucins of known MUC backbones, let alone to which
specific serine or threonine residues, is still very limited.
For example, O-glycans of mucins purified from normal
colon tissue are predominantly core 3 structures with
complex branching. In contrast, O-glycans from colon
cancer cell lines have increases in short O-glycans (Tn
antigen, TF antigen, and sialyl Tn), decreases in O-acetylPhysiol Rev • VOL
sialic acid and sulfation, and increases in sialyl LeX structures (40). However, several mucins are expressed in the
colon, and information describing which O-glycans are
attached to specific MUC protein backbone(s) has not
been reported. Mucins of specific MUC backbones may be
amenable to purification by affinity chromatography with
MUC-specific antibodies.
A similar situation prevails for airway mucins. Over
the last 30 years, several dozen O-glycans have been
cleaved from mucins isolated from sputum from patients
with airway disease and their structures determined by
mass spectrometry or NMR (147). The four major core
types in specific O-glycan structures (Fig. 4) have been
identified in mucins from patients with airway diseases
(278), whereas structural information from mucins isolated from healthy airways has not been reported. The
identities of the MUC mucins to which specific O-glycans
are attached are unknown, as O-glycans were cleaved
from mucin-rich fractions. Thus it is not yet established
whether the complexity of O-glycan structures reflects
altered levels of specific mucins in airway secretions
and/or alterations in glycosylation of specific MUC proteins in disease or inflammation (see sect. IID4). To add to
the complexity, more than one core type O-glycan may be
attached to a single MUC backbone, especially in mucins
that have more than one TR type domain. A comprehensive analysis of O-glycan structures of specific MUC protein backbones will prove useful in determining whether
specific mucins (defined both by MUC backbone and
O-glycan core structures) are altered in airway diseases
consequent to inflammation and/or in a recessive genetic
disease, like CF (148).
While O-glycosylation is predominant in mucins, several MUC proteins contain one or more sites with the
Asn-X-Ser/Thr sequence requisite for N-glycosylation. N-
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FIG. 4. Major core types of mucin
O-glycans. The four major core types of
O-glycans are shown above mucin protein backbones. O-glycan chains are synthesized by specific glycosyltransferases
in a stepwise manner following transfer
of GalNAc to a serine or threonine, elongated by addition of Gal or GlcNAc.
They can be terminally glycosylated by
addition of fucose, sialic acid, or sulfate,
as well as by blood-group determinants.
Mucin O-glycans of known structure are
shown beneath the corresponding O-glycan core structure. a and d: CF lung
mucins (176). b: porcine submaxillary
mucin (42). c: composite structure from
ovarian cyst fluid mucin, in which the
longer branch terminates with two Leb
blood group determinants (165). e and f:
Bronchiectasis lung mucins (31).
252
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
glycosylation typically occurs cotranslationally in the ER;
however, chemical identification of N-glycosides isolated
from mucins secreted in vivo or in vitro has not been
reported. Recently, a newly characterized linkage of Cmannose to tryptophan was identified in MUC5AC and
MUC5B mucins synthesized in vitro (202). Low levels of
mannose have occasionally been reported in secreted
mucins, but they have generally been considered a contaminant. However, if mannose reflects a C-mannose linkage in airway mucins synthesized in vivo, these short
glycans may contribute to the biological or physical properties of airway mucins.
Mucin gene products are identified by nucleotide
probes to specific MUC mRNA sequences or by antibodies
that recognize specific MUC protein determinants. The
sequence of the TR domains of each MUC gene product is
unique (Table 3), which facilitated the use of MUC-specific oligonucleotide probes to evaluate MUC mRNA localization and expression in lower respiratory tract epithelial cells (8, 36, 212).
Antibodies raised against cognate sequences of MUC
TR domains have been used in immunocytochemical
studies to localize MUC protein expression, although antigen retrieval is generally required. However, these antibodies often do not detect mucins on Western blot analyses or ELISA, presumably because extensive O-glycosylation masks the TR epitopes and/or blocks accessibility of
antibodies. In contrast, polyclonal antibodies raised
against cognate sequences in the non-TR domains of secreted mucins identify mature, i.e., glycosylated, mucins
in epithelial secretions by Western blot analyses (225,
271). MUC-specific polyclonal antibodies raised against
cognate sequences in the cysteine-rich domains of
MUC5AC (18, 225, 271), MUC2 (116), and MUC5B (273)
recognize mature secreted airway mucins in epithelial
secretions. Monoclonal antibodies raised against sequences in the non-TR domain of MUC5B and MUC7 and
assayed in salivary secretions have recently been reported (230). Information on MUC-specific polyclonal or
monoclonal antibodies used to investigate human MUC or
rodent Muc mucins in respiratory tract cells or secretions
is provided in Table 4. Detailed information on monoclonal antibodies used to investigate mucin expression in
epithelial tissues and in cancer studies is available (304).
D. Mucin Expression in Epithelial Tissues/Cells
and Airway Cells
Mucin genes are expressed in most epithelial tissues
(85, 287). MUC1 is a pan-epithelial membrane-tethered
mucin expressed at the cell surface in numerous epithelial
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C. Molecular Tools for MUC Identification
tissues, as well as in hematopoietic tissues (85). Expression of all other mucin genes is somewhat, but not exclusively, restricted in healthy tissues (reviewed in Ref. 222)
and can be altered in diseases, especially in cancer (reviewed in Ref. 110). Secreted mucins are typically markers for goblet cells in the surface epithelium and glandular
cells in the respiratory, salivary, gastrointestinal, and reproductive tracts. MUC genes are differentially expressed
in goblet cells in diverse epithelial tissues. MUC5AC is the
predominant mucin normally expressed in goblet cells in
the lung, eyes, and stomach, while MUC2 is expressed in
intestinal goblet cells. MUC5B and MUC19 mucins are
typically restricted to glandular cells.
In the lower respiratory tract, expression of at least
12 human mucin genes (MUC1, MUC2, MUC4, MUC5AC,
MUC5B, MUC7, MUC8, MUC11, MUC13, MUC15,
MUC19, and MUC20) have been observed at the mRNA
level in tissues from healthy individuals. This is reviewed
or described in the following references: MUC1–MUC8
(212, 222), MUC11 (153), MUC13 (302), MUC15 (197),
MUC19 (46), and MUC20 (108). In situ hybridization studies show that ciliated and basal cells in the surface epithelium of the lower (8, 212) and upper (9) respiratory
tract, as well as goblet cells and SMG secretory cells, can
express MUC genes.
In airway tissues from healthy individuals, goblet
cells typically express MUC5AC mRNA or protein, while
glandular mucosal cells express MUC5B and MUC8 (reviewed in Ref. 222) and MUC19 mRNA (46). MUC5B
mRNA, which is typically expressed only in mucosal cells
of SMG and not in goblet cells in tissues from normal
adults, is also expressed in glandular neck cells and some
goblet cells during midtrimester fetal development (212).
Current thinking is that expression of MUC5B gene products in goblet cells in human adult lower respiratory tract
epithelium is atypical and may be a marker of airway
diseases (44). However, MUC5B mucin has also been
reported in goblet cells in normal lung tissues from patients who died without pulmonary involvement (95, 96).
These discrepancies may reflect regional variations
within the airways and will require more attention to the
locus from which tissues are obtained, as well as systematic morphometric analyses.
Interestingly, MUC7 mucin, which is well-expressed
in mucosal and serosal cells in salivary glands (205), is
typically localized to a subset of serous cells in SMG, but
only in 15–20% of airway tissue from normal individuals
(245). Studies on MUC gene expression in tissues from
patients with airway diseases are limited in number and
overviewed in section II.
Mucin expression in the in vitro NHBE and NHNE
model cell systems has also been evaluated in cells derived
from healthy airway tissues (19). Upregulation of MUC3,
MUC4, MUC5AC, MUC5B, and MUC6 mRNA occurs during
differentiation of NHBE cells. MUC1, MUC2, MUC7, and
253
MUCIN GENES AND GLYCOPROTEINS
TABLE
4.
MUC-specific antibodies and airway mucin expression analyses
Antibody
Clone
MUC1
CT1
CT2
M3P
MUC4
ASGP-2
LUM4
PDM4
1G8*
Rabbit pAb
Immunogen
Species Reactivity
Applications
Reference Nos.
Human
W, IHC, IP
163, 201
Human
W, IHC, IP
191
Human
Human
Human
Human
IHC
W
IHC
W
186
163
92
271
Mouse mAb
Mouse mAb
Goat pAb
Mouse mAb
Last 17 AA of cytoplasmic domain:
SSLSYTNPAVAATSANL
Last 17 AA of cytoplasmic domain:
SSLSYTNPAVAATSANL
Core protein backbone
Extracellular domain
COOH terminus
APDTR
Rabbit pAb
NGLQPVRVEDPDGC
Human
W
271
Mouse mAb
Tandem repeat:
HSTPSFTSSITTTETTSHSTPSFTSSITTTETTS
Tandem repeat:
KTTSNSTPSFTSSITTTETTSHS
Human
W
271
Human
IHC
186
ASGP-2 (rat MUC4␤)
Tandem repeat
Tandem repeat
MUC4␤
Rat
Human
Human
Human, mouse, rat
W, IHC
W
W
W, IHC,
ELISA
IHC
W, IP, IHC
178
272
272
77
Hamster mAb
Rabbit pAb
Rabbit
Rabbit
Mouse
Mouse
pAb
pAb
mAb
mAb
MUC4TR
4F12*
MUC5AC
Anti-TR3A
45M1*
Rabbit pAb
Mouse mAb
Tandem repeat
Rat Muc4
Human
Rat⬎mouse⬎human
Rabbit pAb
Mouse mAb
Non-tandem repeat, Cys-rich domains
Gastric mucin M1 protein
Human, mouse
Human, mouse
1–13M1*
LUM5-1;
MAN-5ACI
RGM
HO8
MUC5B
LUM5B-2
Mouse mAb
Rabbit pAb
Gastric mucin M1 protein
Non-tandem repeat: RNQDQQGPFKMC
Human
Human
W
Rabbit pAb
Chicken pAb
Non-tandem repeat, Cys-rich domain
QTSSPNTGKTSTISTT
Human
Mouse
IHC
IHC
Rabbit pAb
Human
W, IHC
107,300
LUM5B-3
Rabbit pAb
Human
W, IHC
300
LUM5B-4
MAN-5BI
Rabbit pAb
Rabbit pAb
Human
Human
W, IHC
W
300
273
PANH2
MUC7
PANH3
MUC8
AntiMUC8
AntiMUC8
MUC13
AntiMUC13
MUC16
OC125
MUC20
AntiMUC20
Mouse mAb
Non-tandem repeat, Cys-rich domain:
RNREQVGKFKMC
Non-tandem repeat, Cys-rich domain:
AQAQPGVPLRELGQVVEC
COOH terminus: PQGFEYKRVAGQC
Non-tandem repeat, Cys-rich domain:
ELGQVVECSLDFGLVCR
Deglycosylated MUC5B
Human
W, IHC
245
Mouse mAb
NH2 terminus: CRPKLPPSPNKPPKFPNPHQP
Human
W, IHC
245
Rabbit pAb
Tandem repeat: TSCPRPLQEGTPGS
Human
W, IHC
242
Rabbit pAb
COOH terminus:
GTPGSGLLPAHIVPLSKSEER
Human
IHC
170
Mouse pAb
Cytoplasmic tail peptide:
CMQNPYSRHSSMPRPDY
Human
IHC, W, IP
302
Mouse mAb
Ovarian cancer cell line OVCA433
Human
IHC
307
Rabbit pAb
NH2-terminal domain:
RGAKRISPARETRSFTK
Human
IHC, W
108
W, IHC
W, IHC,
ELISA
170
229
4,18,225,239
7,194
194
107,271
170
249
IHC, Immunohistochemistry; W, Western blotting; ELISA, enzyme-linked immunosorbant assay; IP, immunoprecipitation. * Commercially
available antibodies.
MUC8 mRNAs are also expressed but do not appear to be
strongly regulated as a function of differentiation. Expression of MUC5B mRNA is localized to goblet cells in these
differentiated NHBE cell cultures that lack SMG (44).
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MUC5B expression in vitro thus differs from expression in
vivo in adult airway tissue, but is similar to expression
patterns observed during development where MUC5B is
expressed in goblet, as well as glandular, cells (212).
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139H2
GP1.4*
C-20*
BC2
MUC2
LUM2–3
MUC3
M3.2, M3.3
Type
254
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
E. Mucins in Airway Secretions/Lung Mucus
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F. Comparative Biology of Mucin Gene Expression
in the Respiratory Tract
Respiratory tract expression of mucin genes in nonhuman species has been investigated mainly in the context of perturbations during disease, especially murine
models. This is overviewed briefly below, and addressed
in more detail in subsections in section II on asthma,
COPD, and CF.
Normal, e.g., naive, murine lungs express membranetethered mucins. Muc1 protein (201) and Muc4 mRNA
(63) have been identified. The glandular secretory mucins
Muc5b (48) and Muc19 (46) have been localized at the
mRNA level to the few SMG located in the proximal
trachea of some murine strains (67). In contrast to human
airways, only rare superficial epithelial cells express
Muc5ac mRNA in naive airway epithelium (55). However,
following allergen sensitization and exposure, Muc5ac
mRNA is well-expressed (4) and Muc5ac mRNA/protein is
localized to allergen-induced goblet cells in the surface
airway epithelium (239). Additionally, mucin gene products typically localized to murine salivary glands, e.g.,
Muc5b or Muc10, are expressed in murine airway goblet
cells induced following allergen sensitization by ovalbumin (OVA) (48) or interleukin (IL)-13 exposure (220),
respectively.
Similar to human airways, rat lungs have been reported to express Muc1 protein (201), Muc2 mRNA (193),
and Muc4 protein (178) in their conducting airway epithelium. Muc5ac protein/mRNA is expressed in rat goblet
cells (103, 118). Expression of other Muc genes has not
been evaluated in rat, as far as we are aware.
To date, there are little data on mucin expression in
other species due to the limited number of Muc clones yet
identified. The Muc1 gene is expressed in hamster lung
(198), rhesus lung (GenBank accession no. AF176947),
and across many other mammalian species (201). The
Muc2 gene is expressed in guinea pig (160) and monkey
(6) lungs. The Muc5ac gene is expressed in guinea pig
(160) and horse (87) lungs. As more mammalian orthologs
of human respiratory tract mucin genes are identified and
characterized, non-murine animal models of chronic in-
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Isolation and characterization of lung mucins have
traditionally utilized the copious amounts of sputum from
patients with airway diseases. However, comparative
studies of mucins in healthy and diseased airways require
procurement of airway secretions or mucus from individuals without airway disease. Healthy individuals produce
much smaller amounts of airway secretions and do not
expectorate mucus, but mucus samples from normal airways can be obtained following a standardized protocol
of hypertonic saline exposure (270). Mucus samples can
also be obtained by endotracheal suctioning of patients
without airway diseases who are undergoing surgical procedures (231).
Identifying specific mucins in airway samples is now
feasible because of the availability of MUC-specific antibodies. The large, cysteine-rich, gel-forming mucins
MUC5AC (116, 194, 271), MUC5B (273), and MUC2 (116)
mucins have been identified immunochemically in induced mucus or bronchial washings from normal airways,
while MUC5AC (179, 194, 223, 271), MUC5B (57, 273, 300),
MUC8 (241, 242), and MUC2 (57) mucins have been identified in sputum samples or bronchial washings from patients with chronic airway diseases.
Comparative analyses of mucin levels are more challenging than simply identifying specific mucins because of
the inherent difficulties in solubilizing mucus or sputum
samples (218) and in determining the best method
(weight, volume, or protein) of normalizing mucin levels.
The limited number of studies carried out are summarized
below and presented in more detail in the disease-specific
subsections in section II. Briefly, MUC5AC and MUC5B
appear to be present at lower levels in mucus from nondiseased airways than in sputum from patients with
asthma, chronic bronchitis, or CF (133). In contrast, in a
recent study in which mucins are normalized on a weight
basis, MUC5AC and MUC5B mucin levels are decreased in
CF sputum compared with normal mucus (107). MUC2
mucin is detected only at very low levels in airway samples from control and diseased airways (116, 133), which
is somewhat surprising as the MUC2 gene is upregulated
in vitro by inflammatory mediators present in the airway
secretions of patients with chronic lung disease (see sect.
IIIB1). As indicated above, this may reflect the less soluble
nature of MUC2 mucin.
Other mucins may be present in airway secretions, as
12 mucins have been identified at the mRNA level in the
lower respiratory tract (see sect. ID). We have recently
shown that MUC7 mucin is expressed in the airway secretions of most asthmatic pediatric patients but is absent
in nonasthmatic pediatric patients (296). Neither levels of
MUC19, a recently identified gel-forming mucin localized
to mucosal cells in SMG (46), nor of MUC8, a mucin
typically expressed in mucosal cells of SMG (242), have
been evaluated in normal or diseased airway tissues or
secretions. The question of whether extracellular glycopeptide fragments of membrane-tethered mucins are
cleaved by proteases and thus present in the mucosal
layer of inflamed or infected airways has also not yet been
evaluated.
Levels of MUC5B and MUC5AC mucin have also been
determined in secretions from differentiated NHBE cells.
MUC5B mucins are present at ⬎10-fold higher levels than
MUC5AC mucins (111), in agreement with the higher level
of MUC5B mRNA expression in vitro (19).
MUCIN GENES AND GLYCOPROTEINS
255
flammatory airway disease will be useful for evaluating
mucin gene regulation and secretory cell remodeling.
II. MUCIN OVERPRODUCTION IN CHRONIC
AIRWAY DISEASES
A. Overview
Mucin glycoproteins function as part of the normal
mucociliary clearance and contribute to the innate immune system in the respiratory tract. Acute challenges to
the respiratory tract, including environmental toxins, allergens, or infectious pathogens, activate lung inflammatory/immune response mediators. Some mediators initiate
mucin hypersecretion by activating a secretory cascade
that results in the rapid release (within minutes) of mucins from secretory granules of goblet cells in the surface
epithelium and/or secretory cells in the SMG (Fig. 5).
These hypersecreted mucins contribute to the innate mucosal defense system by protecting the airway epithelium
in ways that are not yet well understood at the molecular
level. They may entrap particles in the viscoelastic mucus
gel, acting perhaps in conjunction with tethered mucins at
the apical surface of epithelial cells (110), or bind receptors on inflammatory cells using motifs in specific MUC
domains or in O-glycans. For example, the blood group
Leb oligosaccharides associated with MUC5AC gastric
mucin are the primary receptor for Helicobacter pylori in
the human stomach (277). Functional studies on bacterial
Physiol Rev • VOL
interactions with specific O-glycan epitopes in airway
mucins have not yet been carried out.
Sustained mucin secretion, e.g., hypersecretion, requires increased biosynthesis of mucins to replenish secretory granules, which in turn necessitates upregulation
of MUC genes, as well as increased activity of GT or
upregulation of GT genes (Fig. 5). The stimuli for upregulation of MUC genes during acute infection are presumably specific inflammatory/immune response mediators
that are elicited in response to pathogens or environmental toxins, as such mediators upregulate expression of
MUC genes in vitro (see sect. III). The ability of inflammatory mediators to increase expression or activity of GT
and sulfotransferases, enzymes required for mucin biosynthesis (Fig. 1), has been demonstrated (61, 306), but is
far less well studied. Mucin hypersecretion and overproduction typically revert to baseline levels within days,
presumably in response to anti-inflammatory mechanisms
that abrogate proinflammatory mediators and restore homeostasis to the respiratory tract (80).
Airway mucins are overproduced by patients with
chronic airway diseases like asthma, chronic bronchitis/
COPD, and CF that expectorate copious amounts of mucus. In these patients, increased mucin production in the
absence of exacerbation likely reflects GCH in the airway
epithelium, which increases the baseline level of mucin
production (Fig. 5). Inflammatory mediators and by-products identified in the airway secretions or sputum of
patients with chronic airway diseases are implicated in
GCH, which is a characteristic feature and common out-
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FIG. 5. Response of airway secretory
cells to acute or chronic challenges. Inflammatory/immune response mediators
are generated in the lung following exposure of normal human airway epithelium
(top) to environmental irritants. During an
acute attack (bottom right), some mediators can function as secretagogues to activate secretion of mucins from surface
goblet cells and/or glandular secretory
cells. Specific mediators can also upregulate MUC gene transcription, which is a
process required to sustain mucin biosynthesis and thus hypersecretion. Mucin production returns to baseline levels (top) following reestablishment of airway homeostasis by anti-inflammatory mediators
and mechanisms. Patients that develop
chronic airway disease (bottom left) typically manifest goblet cell hyperplasia and
glandular hyperplasia/hypertrophy due to
airway remodeling by inflammatory/immune response mediators, thereby resulting in increased baseline levels of mucin
production in patients with asthma, chronic
obstructive pulmonary disease, or cystic fibrosis. Acute airway challenges or exacerbations contribute to mucus obstruction of the
conducting airways of these patients.
256
TABLE
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
5.
Pathology of airway diseases
Initiators
Inflammatory cells
Thickened basement membrane
Subepithelial fibrosis
Smooth muscle hypertrophy
Bronchoconstriction/hyperresponsiveness
Goblet cell hyperplasia
Asthma
CF
Bronchitis
Allergens, TH2 cytokines
Eosinophils
⫹
⫹
⫹
⫹
⫹
CFTR
Bacteria, neutrophils
⫺
⫹/⫺
⫺
⫹/⫺
⫹
Inhaled toxins, TH1 cytokines
Macrophages, T cells
⫺
⫹
⫹/⫺
⫺
⫹
CF, cystic fibrosis; CFTR, CF transmembrane conductance regulator; ⫹, yes; ⫺, no. Asthma data are from Ref. 75. CF data are from Ref. 104.
Bronchitis data are from Ref. 237.
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duced increases in mucin gene expression reflect regulated MUC/Muc gene expression and/or secretory cell
metaplasia. The latter term is often used generically when
discussing GCH in humans or rats or goblet cell metaplasia (GCM) in murine models of airway diseases. At
present there are no animal models of SMG hypertrophy/
hyperplasia.
B. Mucin Overproduction in Asthma
1. Overview
Asthma, a major cause of chronic illness worldwide,
has increased in prevalence by ⬎80% in all age and ethnic
groups over the past two decades (109, 196). Asthma is
characterized in the airways by inflammation (TH2-driven
eosinophilia), airway hyperresponsiveness, obstruction
by mucus, and remodeling due to fibroblast and smooth
muscle cell proliferation and GCH (38, 75). A hallmark
feature of asthmatic patients who die after an acute exacerbation is the almost complete occlusion of airways by
excessive mucus (3). Mucus plugging does not occur in all
patients dying of asthma; however, incomplete plugs often encrust the airways of chronic asthmatics who have
died from causes other than asthma (253). This indicates
that mucus plug formation is a chronic process in asthmatic patients with varying disease severity, which
progresses to airway occlusion and therefore may be a
major contributor to disease mortality.
Excessive mucus in asthmatic patients reflects overproduction of mucins due to GCH and SMG hypertrophy,
which are major pathological features of asthma. However, GCH is now thought to be a more consistent pathological feature compared with SMG hypertrophy (216).
The latter feature is not common to all patients, even
those with sputum production (120), whereas GCH is the
most characteristic clinical finding even among newly
diagnosed asthmatics (144) and in most (194), but not all
(172), mild and moderate asthmatics. Airway GCH is especially marked in patients who die from status asthmaticus, with a 30-fold increase in the percentage of goblet
cells compared with patients dying from nonasthmatic
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come in chronic airway diseases (Table 5). However, for
each airway disease, specific and unique factors appear to
be responsible for initiating pathways and processes that
ultimately lead to airway obstruction. That GCH reflects
airway remodeling is now an accepted paradigm (75);
however, the mechanism(s) that lead to GCH in specific
airway diseases are not well understood. Briefly, asthma
is a multifactorial disease characterized by airway inflammation, hyperresponsiveness, and GCH/mucus obstruction that is likely initiated by an imbalance of TH cytokines (39, 75). CF airway pathophysiology, which results
from mutations in the CFTR gene, is characterized by
airway inflammation, bacterial infection, neutrophilia,
and GCH/mucus obstruction, but the underlying mechanisms that result in CF airway disease are not yet elucidated (30, 206). Inflammation associated with cigarette
smoke or pollutants likely mediate the development of
GCH in chronic bronchitis. While the etiology and pathogenesis leading to GCH are specific to each airway disease, mechanisms that lead to GCH are likely to converge
at a common pathway.
Patients with chronic airway diseases are susceptible
to exacerbations induced by exposure to allergens or viral
infections. These episodes typically result in massive mucin hypersecretion, presumably because a high number of
goblet and/or mucus cells (due to GCH and/or SMG glandular hyperplasia/hypertrophy) are poised to respond to
the sudden increase in inflammatory mediators. Increased
mucin biosynthesis is likewise easily maintained because
of the high number of MUC templates accessible to inflammatory mediators (Fig. 5). Both processes result in
mucin overproduction and can lead to airway obstruction
by mucus plugs and airway occlusion; therefore, both
likely contribute to the high morbidity and mortality associated with these diseases. Section II, B–D, addresses
current information on mucin overproduction in asthma,
chronic bronchitis, and CF, respectively. The approach
has been to overview information on human pathophysiology with regard to altered mucus cells or mucin production, followed by a summary of studies using in vivo
animal models or in vitro cellular models. In particular,
we have attempted to distinguish whether mediator-in-
MUCIN GENES AND GLYCOPROTEINS
respiratory diseases (3). Thus airway remodeling by GCH
alters airway mucin composition, contributes to the obstruction of the conducting airways with mucus, and culminates in obstruction of the airways with mucus plugs,
thereby greatly contributing to the severity of asthma (21,
109, 123, 215, 216, 224, 286).
2. MUC mRNA and protein in asthmatic cells
3. MUC mucins in asthmatic secretions and
mucus plugs
Overproduction of airway mucins in asthmatic patients is a well-established paradigm clinically, and “mucus abnormalities” are considered a feature of asthma.
However, as recently pointed out in a seminal review
(216), it is not yet established whether these abnormalities result from overproduction of specific mucins, an
intrinsic biochemical abnormality in asthmatic mucins, or
interactions between mucins and other mucosal components.
Studies to date have focused on the secreted cysteinerich mucins: MUC5AC, MUC5B, and MUC2. MUC5AC and
MUC5B mucins have been identified in asthmatic airway
secretions. MUC5AC mucin, initially isolated as tracheobronchial mucin from the lung mucus of a patient with
bronchial asthma (179, 223), was subsequently shown to be
present in airway secretions from both healthy individuals
and asthmatic patients (116, 194, 271). MUC5B mucin has
also been identified immunochemically and biochemically in
asthmatic sputum, as well as in normal airway mucus (273,
Physiol Rev • VOL
300). Overall, MUC5AC and MUC5B mucin levels appear
higher in secretions from asthmatic airways compared with
nondiseased airways (133), likely reflecting GCH as well as
SMG hypertrophy/hyperplasia in some asthmatic patients
(216).
MUC2 mucin is present at very low levels in normal
or asthmatic airway secretions (57, 116, 133), although it
is well-detected in gastrointestinal tract secretions using
the same antibody (271). Because MUC2 mRNA expression is increased ex vivo in human bronchial explants
from nondiseased airway tissues (157) and in vitro in
airway epithelial cell lines (13) by inflammatory mediators present in asthmatic airway secretions, it is surprising that MUC2 mucin is only a minor component of asthmatic airway secretions. This may reflect difficulties in
clearing “insoluble” MUC2 mucin from the airways. MUC2
is considered to be an almost insoluble mucin, which
protects the intestinal epithelium against damage (10).
This likely reflects the very large TR domain of MUC2,
which is not interspersed by cysteine-rich domains, in
contrast to MUC5AC and MUC5B mucins (Fig. 3), which
predominate in the airways. Interestingly, MUC2 mucin is
detected in a higher percentage of secretions from asthmatic patients (3/10) than from induced sputum of healthy
individuals (1/11) (133), suggesting that analysis of MUC2
mucin warrants further analysis in a larger cohort of
patients.
Recent biochemical data indicate that MUC7 mucin
is present in the airway secretions of asthmatic, but not
nonasthmatic, pediatric patients (296). Other secretory
mucins (MUC6, MUC8, and MUC19) may be present in
asthmatic secretions but have not yet been evaluated.
The molecular identity of mucins in asthmatic mucus
obtained from inspissated airways following exacerbations has not been thoroughly investigated. A study carried out to biochemically investigate mucins from a patient who died in status asthmaticus (248) later identified
MUC5B mucin in the mucus plug (246). MUC5AC and
MUC5B mucins have been identified immunohistochemically in the lumen of patients with fatal asthma (94). A
systematic evaluation of mucins that comprise the mucus
plugs occluding the airways of patients who have died in
status asthmaticus would be useful. The resultant data
would provide fundamental information on mucin profiles
following asthmatic exacerbations and thus direct future
studies on regulation of MUC gene(s) activated by inflammatory/immune response genes during asthmatic exacerbations.
4. Genetic association of MUC genes and asthma
Genetic studies on mucin genes have been carried
out to evaluate the potential involvement of mucins in
airway obstruction in asthma and other airway diseases.
Polymorphisms in the number and lengths of TR in
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Expression and localization of some secretory mucins have been evaluated in airway tissues from asthmatic
patients. Localization of MUC5AC mRNA or protein expression is not altered in airway cells of asthmatic patients, since MUC5AC gene products are restricted to
goblet cells in normal (8, 212) and asthmatic (94) airway
epithelium. However, a marked increase in MUC5AC expression has been observed in asthmatic epithelial samples obtained by fiberoptic bronchoscopy and bronchial
biopsy (112), and a trend toward overexpression of
MUC5AC mRNA has been observed in goblet cells of
bronchial brushings of asthmatic patients (194).
On the other hand, altered localization of MUC5B
gene products has been noted in airway tissues from
asthmatic patients where MUC5B is expressed in goblet
cells and glandular neck cells, as well as in mucosal SMG
cells (94). Because dual localization of MUC5B in surface
epithelium and mucosal glandular cells occurs during
midtrimester fetal development (212), mediators in asthmatic airways may recapitulate events that occur during
development. Neither MUC2 nor MUC19 mRNA/protein
expression has yet been evaluated in asthmatic airway
tissues, although MUC2 mucin has been evaluated in airway secretions, as discussed in the following subsection.
257
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MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
MUC1, MUC2, MUC4, MUC5AC, and MUC5B genes have
been identified. Additionally, polymorphisms have been
evaluated in atopic patients with or without asthma. No
correlations of VNTR polymorphism in MUC1, MUC4,
MUC5AC, or MUC5B genes were observed in patients
with asthma, although a longer allele in the MUC2 gene is
associated with a cohort of atopic, nonasthmatic patients
(284). In contrast, an association of asthma with the
MUC7 gene is reported, with a significantly lower frequency of the MUC7*5 allele in a small cohort of Northern
European asthmatics (132).
Mice have proven useful models over the last decade
for investigating the pathogenesis of allergic asthma. In
vivo studies using OVA sensitization and challenge or
direct cytokine exposure have linked Th2 cytokine-mediated inflammation and GCM. IL-13 is a central mediator of
GCM in murine models of allergic asthma (97, 140, 303),
and GCM induced by other Th2 cytokines is stimulated
through a common, IL-13-mediated pathway (299). GCM
is a characteristic phenotype used to monitor the pathophysiology of asthma, since goblet cells are very rarely
seen in the airway epithelium of naive mice, while airway
goblet cells predominate in mice exposed to inflammatory
or immune-response mediators. Briefly, mice exposed to
single or multiple doses of allergen or IL-13 develop GCM
within 1–3 days after one or more allergenic challenges (4,
239, 303), although a few goblet cells are evident by 6 h
after a single exposure to IL-13 (239) or OVA challenge
(74).
Without continual exposure to allergens, GCM is
transient in murine airways, although the temporal processes are impacted by allergen or mediator, dose, and
murine strain. The epithelium reverts nearly to baseline
levels 11 days after multiple challenges with OVA (22) and
GCM, which is maximal at 3 days after a single OVA
exposure, is minimal 8 days following OVA exposure
(239). IL-13-induced GCM also reverts to baseline following multiple IL-13 exposures (97, 140, 303). Taken together, these results suggest that sustained GCM requires
ongoing exposure of the airways to IL-13, either directly
or indirectly following an allergenic exposure, and that a
fairly rapid reversal of the processes leading to GCM
occurs in the absence of IL-13 or genes activated by IL-13.
Thus GCH manifested in patients with asthma or obstructive airway diseases may also be reversible if allergens or
inflammatory mediators are removed or inhibited. If this
were not so, the prevalence of GCH would be nearly 100%
at any time in allergenic environments, whereas in the
absence of environmental insults, GCH can revert to a
normal morphology in conducting airways (238).
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5. Goblet cell metaplasia and mucin gene expression
in murine models of asthma
Ligand binding of IL-13 to the IL-4R␣/IL-13 receptor
activates Stat6, which is a key regulator of IL-13-mediated
GCM (140, 141). While the downstream genes and pathways that lead to GCM in murine models of allergic
asthma remain to be identified, Foxa2, a winged helix
transcription factor, is implicated in this pathway as mice
that lack Foxa2 manifest GCM (294). Mechanisms that
contribute to the reversal of GCM in rodents are also
being investigated. Members of the Bcl-2 family, which
inhibit apoptosis, play a role in restoring a metaplastic
airway epithelium to a normal phenotype following allergenic challenges (250). A better understanding of the
mechanisms that directly initiate or reverse GCM in murine airways may lead to pharmacological intervention
that would ultimately decrease or circumvent GCH, and
thus airway obstruction by mucus in human airways.
Cytokine-induced GCM correlates with increased expression of Muc5ac, an airway goblet cell marker. However, this correlation is not a demonstration that the
cytokine of interest regulates mucin gene expression. For
example, IL-4 (269) and IL-9 (171) are reported to increase
Muc5ac gene expression and mucus production in vivo,
but this likely reflects the IL-13-induced increase in goblet
cells (299), which endogenously express Muc5ac mRNA/
protein, rather than cytokine regulation of mucin gene
expression. IL-4 does not upregulate MUC5AC/Muc5ac
gene expression; the IL-9 story is less clear (Table 6, see
sect. IIIC). In addition to inducing GCM in murine airways,
IL-13 may, however, directly or indirectly upregulate
Muc5ac gene expression, as IL-13 increases the promoter
activity of Muc5ac following transfection of a Muc5acpromoter-luciferase plasmid into murine transformed
Clara cells (74). However, IL-13 does not upregulate
MUC5AC mRNA expression in three human lung cancer
cell lines (226) or in differentiated NHBE cells (45), suggesting differences in the sequences or regulation of
Muc5ac and MUC5AC promoters.
Muc5b mucin is also induced in an OVA model of
allergic asthma and mRNA expression is localized to goblet cells in the airway epithelium (48). Muc2 mRNA expression is induced in OVA and IL-13-induced models of
allergic asthma (239). Muc10 mRNA and protein are also
upregulated in murine airway epithelium and expressed
in goblet cells induced by IL-13 exposure (220, 296). Thus
several mucin genes are expressed in secretory cell metaplasia. Taken together, these data suggest that murine
models of allergic asthma are pertinent to human asthma
with regard to expression of secreted mucin gene products (see sect. IIB3). Thus mechanisms that direct GCM in
murine models of allergic asthma are likely to provide
insight into GCH in human models in vitro and warrant
further investigation.
Two models of chronic asthma in which GCM is
sustained and not transient have recently been established and may prove useful in investigating pathways
MUCIN GENES AND GLYCOPROTEINS
C. Mucin Overproduction in COPD
1. Definition of COPD/chronic bronchitis:
the inflammatory milieu
COPD is defined clinically as a complex of diseases
characterized by airflow obstruction due to chronic bronchitis or emphysema. It is the fourth leading cause of
patient deaths in adults in the United States. Approximately 14 million people in the United States have COPD;
the majority of these patients have chronic bronchitis
(237). The diagnostic criteria for chronic bronchitis are
the presence of cough and sputum on most days for at
least 3 mo per year in two consecutive years without
another explanation (5). Epidemiologically, the major risk
factor associated with the development of chronic bronchitis is exposure to environmental inhalant toxins, especially cigarette smoke. Exacerbations of airway disease
may be provoked by viral or bacterial infections or by
exposure to air pollutants.
The central airways of patients with chronic bronchitis are chronically inflamed with increased numbers
of macrophages and T lymphocytes (237). Corresponding to the cellular inflammatory profile, there are increased levels of IL-6, IL-1␤, IL-8, tumor necrosis factor-␣ (TNF-␣), and monocyte chemotactic protein-1 in
induced sputum or bronchoalveolar lavage from patients with stable COPD (52). During acute exacerbations, neutrophils and neutrophil chemokine and receptor expression increase in the airways of COPD patients (211). Neutrophils and macrophages release
proteases that contribute to the inflammatory milieu
and overwhelm antiprotease defenses. In addition, reactive oxygen species (ROS) generated by cigarette
smoke or by inflammatory cells may produce airway
Physiol Rev • VOL
and parenchymal injury (237). Together, these mediators injure the airway, activating programs for remodeling (including GCH) and/or MUC gene regulation.
2. Mucin changes in vivo
A major pathological feature of chronic bronchitis is
an increase in secretory cells due to hypertrophy of SMG
and to GCH, which can extend to the peripheral airways.
Secretory cell hyperplasia is a prerequisite for sustained
mucus hypersecretion/mucin overproduction. These phenotypes are a significant component of airway obstruction in chronic bronchitis and directly correlate with reduced pulmonary function (283).
Altered cellular localization and increased expression of mucins have been reported in patients with
COPD. In airway tissues from patients with obstructive
airway diseases, MUC5B mRNA is expressed in goblet,
as well as glandular, cells, while MUC5B is not expressed in goblet cells of control patients. MUC5B
mRNA is also expressed in the goblet cells of differentiated NHBE cells derived from these patient tissues,
but expression levels are similar in cells from control
patients and patients with obstructive airway diseases
(44). In another study, no differences in alcian blue or
periodic acid Schiff (PAS) staining are observed in
peripheral lung sections from 9 smokers with COPD, 11
age-matched controls including smokers, and 6 lifelong
nonsmokers with normal lung function, although intraluminal PAS staining is significantly more frequent
among COPD subjects. MUC5AC protein expression is
significantly higher in the bronchiolar epithelium of
patients with COPD, and MUC5B expression is increased in the bronchiolar lumen MUC5B of COPD
patients relative to controls (41).
Airway mucins from chronic bronchitis patients
overall are similar in size and structure to mucus from
healthy individuals, but appear to be less acidic (56).
However, glycosylation patterns vary during acute exacerbations, as chronic bronchitis mucins are highly
sialylated with increased sialylated and sulfated Lex
structures (147). Despite biochemical characterization
of the mucus gel, information about specific mucin
glycoproteins in chronic bronchitis airway secretions is
limited to a few studies. MUC5AC and MUC5B mucins
are highly expressed constituents both in normal and
chronic bronchitis mucus (133). The ratio of MUC5B:
MUC5AC is increased, and MUC5B differs in charge in
chronic bronchitis sputum compared with normal airway mucus (133). These observations suggest that both
goblet and SMG cell secretions contribute to the mucus
hypersecretion observed during exacerbations of chronic
bronchitis.
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that maintain GCH. In an OVA-induced model, airway
remodeling manifested by GCM persists after resolution of acute allergen-induced airway inflammation
(152). In a virally induced model, GCM develops following infection of murine airways with Sendai virus (SV)
and subsequent viral clearance (293). Sendai virus, a
murine RNA virus of the family Paramyxoviridae, is a
natural pathogen of mice and causes reversible bronchiolitis and pneumonia in susceptible strains of mice
(35, 199, 261), which parallels clinical features of childhood and adult asthma in the lower respiratory tract
(149, 298). GCM is maintained for more than a year in
C57BL/6 mice following SV infection, suggesting that
genes and pathway(s) that lead to a chronic asthma
phenotype are activated and maintained by the murine
host in response to infection by a murine virus. Related
work in rat strains has shown that Brown Norway rats
are more likely than F344 rats to develop an asthma
phenotype following SV inoculation (258).
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MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
3. Mucin regulation by inflammatory mediators
in vitro and in vivo in animal models
of chronic bronchitis
Physiol Rev • VOL
D. Mucin Overproduction in CF
1. The “mucus abnormality”
CF was initially called “mucoviscidosis” because of
copious amounts of “mucoproteins” in the respiratory and
gastrointestinal tracts of CF patients (76). Evidence for a
fundamental mucus abnormality in CF is supported by
ultrasound studies, wherein 90% of CF fetuses during the
17- to 19-wk period of gestation manifest inspissated
meconium in the distal ileum, which is generally reabsorbed by birth (68). Gastrointestinal mucus obstruction
is not life threatening except to the small number of CF
infants born with meconium ileus.
In contrast, mucus obstruction in CF airways occurs
postnatally (309), even though pulmonary complications
resulting from airway mucus obstruction and predisposition to infection are the major cause of morbidity and
mortality in CF patients (297). There are no marked morphological abnormalities in the airways of CF fetuses or
neonates and the numbers and distributions of goblet
cells in the epithelium, as well as the numbers and sizes of
SMG, are within normal ranges at birth (263). Dilated
acinar and duct lumens in SMG are observed in CF airways early in life; the earliest consistent pathological
lesion and evidence of mucus obstruction presents in the
bronchioles (262).
CF is a recessive genetic disease caused by mutations
in the CFTR gene, which encodes the cystic fibrosis transmembrane regulator glycoprotein, CFTR (213). CFTR is
expressed in mucus-rich epithelial tissues (respiratory,
gastrointestinal, and reproductive tracts), non-mucus rich
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Because cigarette smoke is the single common factor
related to development of chronic bronchitis, several in
vivo models have been established to investigate the
mechanism of smoke-induced airway inflammation and
secretory cell metaplasia. Either inhaled tobacco smoke
or cigarette smoke extract induce secretory cell metaplasia in rat main stem bronchi (146) or in BALB/c mice
airways (181). In mice, exposure to smoke increases neutrophilic inflammation, mucin expression, and airway reactivity to methacholine. An aldehyde component of cigarette smoke, acrolein, induces expression of Muc5ac
gene in vivo in rat (27) and mouse (28) lungs, concomitant
with secretory cell metaplasia. In mice, these effects are
dependent on macrophage, rather than neutrophil, inflammation (28). One mediator that regulates the secretory
metaplastic response to cigarette smoke in guinea pig
airways is platelet activating factor (137).
Air pollutants also induce secretory cell metaplasia
in animal models in vivo. Sulfur dioxide exposure induces
superficial secretory cell hyperplasia in rats (145) and
mucus gland hypertrophy in dogs (236). Ozone induces
mucus cell metaplasia in rat nasal airway epithelium
(106). Neutrophil elastase (NE) proteolytic activity stimulates bronchial secretory cell metaplasia in hamsters
(32) and in mice (288). It is noteworthy that inflammation
associated with cigarette smoke or pollutants appears to
mediate the development of secretory cell metaplasia.
This concept is supported by evidence that glucocorticoid
treatment mitigates the effect of cigarette smoke (214) or
ozone (113) on secretory cell metaplasia.
Bacteria, including Staphylococcus aureus (S. aureus), Streptococcus pneumoniae (S. pneumoniae), and
Haemophilus influenzae (H. influenzae), are common
pathogens that trigger exacerbations of bronchitis. Bacterial products regulate mucin gene expression in epithelial cell lines in vitro, as discussed in section III. In vivo,
endotoxin or lipopolysaccharide (LPS), a component of
Gram negative bacterial cell wall membranes, increase
goblet cell number in rat nasal epithelia (251) and in
murine respiratory epithelia (306). Endotoxin also enhances ozone-induced secretory cell metaplasia in rat
nasal epithelia (292), suggesting that infections and pollutants synergize to exacerbate secretory cell metaplasia.
Paramyxoviruses also induce secretory cell metaplasia
in vivo as a separate trait independent of intracellular
adhesion molecule (ICAM)-1 expression and acute inflammation in a chronic model of murine asthma (293). These
studies demonstrate the powerful effect of infectious
agents on the induction of secretory cell metaplasia,
thereby resulting in increased mucin production since
goblet cells endogenously express mucin genes and secrete mucin glycoproteins.
The complement of inflammatory mediators expressed in the airways of patients with stable COPD and
asthma are different, as TH1 cytokines predominate in
COPD and TH2 cytokines predominate in asthma (Table
5). Interestingly, viral infections, cigarette smoke, and
pollutants cause exacerbations in both patient populations, which are marked by neutrophil inflammation. Mucus secretion is an important component of the innate
immune system. Therefore, teleologically, it is possible
that both TH1 and TH2 cytokines regulate mucin gene
expression and secretory cell metaplasia in vivo and that
individual cytokines have different functions in epithelial
and immune cells. These possibilities are being investigated by numerous laboratories, and current data on mucin gene expression are presented in Table 6. It is likely
that some mediators synergistically interact with pollutants, infectious agents, and neutrophilic mediators to significantly enhance remodeling that culminates in mucin
overproduction and hypersecretion in airway disease
states.
MUCIN GENES AND GLYCOPROTEINS
Physiol Rev • VOL
clearance will require a more comprehensive understanding of the multifunctional roles of CFTR, as well as of the
roles of mucins in healthy and CF airways (206).
2. Mucin mRNA/protein expression in CF cells
There is limited information on quantitative comparisons of mucin gene and protein expression in CF and
control airway cells and secretions. One study examining
mucin gene expression in uninfected nasal cells from CF
versus control subjects reports altered ratios of MUC5AC:
MUC2 mRNA expression in CF cells (290). In situ hybridization studies show altered expression and localization
of MUC2 (157) and MUC5AC (66) mRNA in CF versus
non-CF bronchial explants and increased expression of
mucin genes in response to P. aeuroginosa. Briefly,
MUC2 mRNA is sparsely detected in the surface epithelium and is not detected in the SMG of non-CF specimens,
but is expressed both in the surface epithelium and SMG
of CF specimens. Exposure of bronchial explants to P.
aeuroginosa supernatant results in a marked increase of
MUC2 mRNA expression in the SMG of both patient
groups (157). MUC5AC mRNA is expressed in cells of the
surface bronchial epithelium of both CF and non-CF specimens, minimally expressed in the SMG of non-CF specimens, and, surprisingly, highly expressed in the SMG of
CF specimens. Exposure of bronchial explants to P. aeuroginosa supernatant results in a marked increase of
MUC5AC mRNA expression in both the surface epithelium and the SMG of control patients (66). These results
are intriguing, as MUC5AC gene products are not typically
observed in SMG (8, 212). In contrast, no differences in
the cellular localization of MUC5AC or MUC5B protein
expression are observed between CF and non-CF lower
respiratory tract epithelial biopsies (95). MUC5AC mucin
is expressed in goblet cells and MUC5B in SMG mucus
cells. However, MUC5B is also expressed in goblet cells in
biopsies from both CF and healthy patients (95).
3. MUC mucins in CF airway secretions
MUC2 mucin glycoprotein is barely detectable in normal (115, 116) or CF airway secretions (57, 133), although
MUC2 mRNA is well expressed in CF bronchial explants
and its expression is upregulated by P. aeuroginosa LPS
(157) (see sect. IID2). MUC2 is considered an “insoluble”
mucin (10), however, and may not be easily cleared by the
airways.
On the other hand, MUC5AC and MUC5B mucins,
which are well-expressed at the mRNA level in airway
tissues, are major components of secretions and mucus
from healthy airways as well as from sputum samples
from patients with CF. The levels of these two mucins in
CF sputum and non-CF mucus have been evaluated in two
studies, with conflicting results. An initial study reported
that MUC5AC and MUC5B are major mucins present at
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tissues (sweat glands and kidney), as well as nonepithelial
tissues (heart and brain) (274). However, obstruction is
typically observed only in mucus-rich tissues. The question of how CFTR initiates the primary pathogenetic event
in CF airways is still unresolved and remains a question of
paramount interest. There are several current hypotheses
on the pathogenesis of CF lung disease. 1) Expression of
mutant CFTR in CF respiratory cells produces defective
chloride secretion and elevated sodium absorption (29),
resulting in altered salt concentrations in airway secretions. However, the question of whether salt concentrations in CF airways are hypotonic or hypertonic is still
unresolved (98, 268). 2) The concept that alterations in
mucus volume impact on mucus hydration, and thus on
the rheology of CF airway mucus to increase susceptibility to infection in CF airways, continues to gain credence
(30). A marked decrease in the airway surface liquid
volume in CF bronchial explants in vitro reflects the
abnormal ion transport properties of CF airway epithelia
in vivo (175). Similar behavior, as well as increased
amounts of mucus and altered mucus transport and mucus adhesion to airway surfaces, is observed in vivo in
mice that overexpress the ␤-subunit of the epithelial sodium channel, ENaC (174). 3) Lack of functional CFTR in
lung cells could engender a hyperinflammatory state that
alters homeostasis in CF airways. Such a situation is
indicated by intrinsically high levels of inflammatory mediators in the airways of CF infants in the absence of
evidence of previous infection (11, 127, 138, 184, 189).
Many of these mediators increase expression of mucin
genes in vitro (Table 6) and thus could prime CF airways
for mucin overproduction in vivo, contributing to recurring cycles of infection followed by increased expression
of mucins that culminates in airway obstruction with
mucus. 4) If airway obstruction with mucus occurs before
infection, then a primary or early result may be hypersecretion or accumulation of secretions with abnormal
properties (297). This could include altered levels of CF
mucin glycoproteins, as discussed in section IID3, or expression of CF mucins with alterations in terminal glycosylation, as discussed in section IID4. 5) Alternatively,
mutant CFTR could lead to overexpression or altered
regulation of specific glyconjugates that alter the ability of
airway epithelium to protect against Pseudomonas and
thus lead to obstruction with mucus. The glycolipid asialo
GM1, a receptor for P. aeuroginosa pilin, is expressed at
higher levels in CF than non-CF primary airway epithelial
cells (233). Interestingly, the extracellular domains of the
MUC1 mucin protein backbone bind to P. aeuroginosa
flagella (161), resulting in phosphorylation of specific
serine residues in the cytoplasmic tail of MUC1 and activation of the extracellular signal-related kinase (ERK)
(162), suggesting a role for tethered mucins in CF airway
defense. An explanation of how mutant CFTR leads to
inflammation, chronic infection, and reduced airway
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MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
4. Alterations in terminal glycosylation of O-glycans
Several studies support altered glycosylation of CF
mucins, although this remains to be conclusively demonstrated. Initially, studies focused on mucoprotein fractions from the duodenum, where increased levels of fucose and sulfate and decreased levels of sialic acid in CF
samples relative to non-CF samples are observed (65).
These data were reinforced in later analyses of CF mucosal samples (reviewed in Refs. 217, 234). Increased sulfation in CF glycoconjugates has also been reported (49,
308). The structures of several dozen neutral, sialylated
and sulfated O-glycans from airway mucins of patients
with CF or bronchitis have been determined (49, 114, 134,
166). A consistent finding has been increased expression
of sialyl-Lex epitopes in mucin-rich fractions isolated from
patients with CF. However, a similar finding has also been
observed in mucins isolated from patients with chronic
bronchitis, leading to the suggestion that increased sialylLex expression in airway mucins correlates with severe
infection or inflammation (59).
In support of a CF-specific alteration in terminal
mucin glycosylation, sialylated and fucosylated structures
Physiol Rev • VOL
in MUC5B mucins in salivary secretions from CF and
non-CF individuals have been compared. Lectin staining
demonstrated a shift from sialic acid ␣2,6 linkages in
normal MUC5B mucins to sialic acid ␣2,3 linkages (Lex
structures) in CF MUC5B (252). Because salivary glands
are typically not infected in CF patients, the increased
expression of sialylated Lex structures in MUC5B, if validated by structural studies of MUC5B O-glycans, would
demonstrate a genetic consequence of mutated CFTR on
glycosylation, rather than a consequence of infection/
inflammation. However, MUC19, which has recently been
shown to be expressed in salivary glands (46), may well
be present in salivary secretions, which would confound
analysis of large secreted mucins.
A recent study compared O-glycans isolated from
mucins secreted in vitro by differentiated NHBE cells
from CF and healthy individuals (111). Carbohydrate
composition patterns are similar in CF and non-CF Oglycans. However, few structures are reported, preventing
a comparison of terminal glycosylation. Interestingly, Oglycans have all four core types present, likely reflecting
the mixture of MUC5B (both high- and low-charge glycoforms) and MUC5AC mucins. Thus the question of altered
glycosylation between CF and non-CF mucins with the
same MUC protein backbone is still not resolved, either
for mucins secreted in vivo or in vitro. Elucidating the
significance of alterations in terminal glycosylation in CF
mucins will require molecular analyses of O-glycans released from specific MUC mucins isolated from CF and
control individuals.
Biochemical and structural data on membrane glycoproteins from CF cells also continue to support differences, especially in altered fucosylation, in posttranslational modifications in CF glycoproteins expressed in epithelial cells, although the reported differences are on
N-glycans (91, 234).
Differences in glycosylation of CF proteins could
reflect alterations in GT activity, expression, or compartmentalization and could be a consequence of mutant
CFTR, which is reported to alter the acidic microenvironment in the ER and Golgi (12), the sites of posttranslational glycosylation of secreted and membrane proteins.
The concept of altered acidification in CF cells is not
supported in later investigations, however (89). On the
other hand, inflammatory mediators increase expression
of several glycosyltransferases and sulfotransferases in
vitro (61). Activation of an ␣1,3-fucosyltransferase, different from the Lewis enzyme ␣1,3-fucosyltransferase III,
has been suggested to explain the increase in sialyl-Lex
epitopes in severely infected patients phenotyped as
Lewis negative (59). Additionally, the paucity of sialic
acid ␣2,6 linkages in CF MUC5B salivary mucin (252)
suggests a decreased expression, activity, or compartmentalization of one or more ␣2,6 sialyltransferases in CF
secretory cells in vivo. Structural analyses of O-glycans
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variable concentrations in CF sputum and in airway mucus obtained from normal airways following exposure to
hypertonic saline. These data indicate that both mucins
are elevated in CF sputum and that the low-charge form of
MUC5B is increased in CF sputum (133). However, a more
recent study, in which mucus and sputum were processed
similarly and normalized per volume, weight, or protein,
indicate that MUC5AC and MUC5B mucins are present in
lower concentrations in CF sputum (107). While this suggests reduced mucin secretion by CF cells, proteases
present in CF sputum are able to digest lung mucins in
vitro (221) and may fragment or remove an epitope in the
cognate sequence, thereby reducing detection by antibodies. However, antibodies raised against the same cognate
sequence were used in both studies (107, 133). Thus differences in procurement, processing, and normalization
of mucus and sputum samples may account for the conflicting conclusions. Overall, comparative studies of mucus and CF sputum samples are confounded by the presence of chronic inflammatory cells and mediators in CF
subjects that impact on mucin production and characterization, thereby rendering reliable quantitation of mucin
gene and glycoprotein expression in the uninfected and
uninflamed CF lower respiratory tract difficult.
Levels of MUC5B and MUC5AC mucins have also
been compared in secretions from differentiated NHBE
cells established from lung tissues of control and CF
patients. MUC5B and MUC5AC levels are similar in NHBE
cells from both patient populations, with MUC5B mucins
present at ⬎10-fold higher levels than MUC5AC mucins
(111).
MUCIN GENES AND GLYCOPROTEINS
5. Models of airway obstruction in CF
In contrast to the murine models of allergic asthma
discussed in section IIB5, murine models of CF for investigating airway mucus obstruction have proven more difficult to generate. Mice typically lack airway SMG, and
serosal cells in SMG glands are considered the major site
of expression of CFTR in human airways (71). Mice that
are deficient in Cftr, e.g., CF mice, do not mimic the
physiology or pathology of CF airways, since the chloride
channel abnormality observed in the airways of CF patients is not manifested in the airways of CF mice (255). P.
aeuroginosa (55) or S. aureus (254) do not colonize the
airways of CF mice. Furthermore, CF and heterozygous
mice, which exhibit GCM following OVA challenge, clear
both types of bacteria (55). However, mice that overexpress the ␤-subunit of ENaC mimic many of the phenotypes observed in CF airways (174), indicating that these
transgenic mice may be a useful model for investigating
the pathogenesis of CF airway disease.
Obstruction of the intestinal lumen with mucus occurs in CF mice, however, where the CF chloride secretion abnormality is manifested (255). Muc1 contributes to
obstruction with mucus in the gastrointestinal tract, as
mice that lack Cftr and Muc1 exhibit greatly diminished
intestinal obstruction and have better survival compared
with mice that lack only Cftr (200).
III. REGULATION OF MUCIN GENES
A. Overview
Respiratory tract infection and inflammation are
characteristic features of patients with asthma, COPD, or
Physiol Rev • VOL
CF. Bacterial or viral interactions with host cells trigger
the activation of signal transduction pathways that modulate host responses and increase expression of inflammatory genes. Many inflammatory/immune response mediators, e.g., the pro-inflammatory mediators TNF-␣, IL-6,
IL-8, and by-products of bacterial or inflammatory cells,
e.g., LPS or neutrophil elastase (NE), are elevated in
airway secretions of patients with chronic airway disease
(25, 52, 126, 184, 195). Investigations over the last decade
have tested and validated the hypothesis that inflammatory/immune response mediators also regulate mucin
gene expression in vitro (Fig. 6), thereby directly linking
infection and inflammation to the copious amounts of
mucus produced in chronic airway diseases (reviewed in
Refs. 13, 226).
Current data on mucin gene regulation are depicted
in Figure 6, summarized in Table 6, and presented in
section III, B–D. Most studies have been carried out in
airway epithelial cancer cell lines and/or primary differentiated NHBE cells. They support the paradigm that
certain mediators 1) selectively regulate expression of
specific MUC genes at steady-state equilibrium in airway
epithelial cancer cell lines and/or primary differentiated
NHBE cells and 2) regulate expression of individual MUC
genes at the transcriptional and/or posttranscriptional
level. Pathogen by-products, inflammatory/immune response mediators, and growth factors, such as the epidermal growth factor (EGF), upregulate mucin genes expressed in airway epithelial cells, as reviewed in section
III, B and C. Mucin gene regulation studies initially focused
on MUC2, since nucleotide sequences for MUC2 cDNA
and promoter were available well before the MUC5AC
and MUC5B genes were cloned and characterized.
Many mediators that upregulate MUC2 gene expression also upregulate MUC5AC, as well as MUC8 or MUC4,
genes (Table 6). However, many of these mediators [TNF␣, prostaglandin E2, 15-hydroxyeicosatetraenoic acid, or
phorbol 12-myristate 13-acetate, a protein kinase C (PKC)
activator] do not upregulate MUC5B gene expression
(26), even though MUC5B mucin, unlike MUC2 mucin, is
present at high levels in mucus from healthy and diseased
airways (see sect. II). On the other hand, IL-6/IL-17 (45),
UTP (47), and IL-8 (15) upregulate MUC5B, as well as
MUC5AC, suggesting differential and specific regulation
of mucin genes by inflammatory/immune response mediators. Considerable information is now known about
some signal transduction pathways through which mucin
gene expression can be mediated (Fig. 6). Minimal information is available on the specific cis-sequences in MUC
promoters to which activated transcription factors bind to
regulate MUC gene expression. Investigations on posttranscriptional regulation of mucin genes are also limited
(see sect. IIID). Further investigations into transcriptional
and posttranscriptional regulation of airway mucin genes
are warranted to better understand the pathways and
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from MUC5B mucins secreted in vivo by CF patients and
controls would clarify the significance of these findings.
Secretion of CF mucins with alterations in terminal
glycosylation could alter the physical (rheological or viscoelastic) properties of airway mucus, as sialic acid and
sulfate impart anionic properties to mucins, while fucosylation imparts hydrophobic properties. Additionally, alterations in the extent of O-glycosylation, e.g., number of
chains per mucin protein backbone or the size or structure of O-glycans, could impact the biophysical or biological (binding to bacteria, viruses, cells) properties of specific mucins. Indeed, terminal ␣1,4-linked N-acetylglucosamine in O-glycans, which is expressed in the cells in
gastric glands where MUC6 is synthesized, has a natural
antibiotic function against Helicobacter pylori infection
(125). Studies on biophysical and biological properties of
specific airway MUC mucins with defined O-glycan chains
will be facilitated when adequate amounts of purified or
recombinant MUC mucins or specific MUC domains are
available.
263
264
TABLE
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
6.
Regulation of human MUC gene expression
Agonist
MUC Gene
P. aeuroginosa or LPS
2
Mechanism
Cell Line
RNA/Prt*
Reference Nos.
Bacteria, bacterial products, and viruses
2
5AC
5AC
2
H. influenzae
2
2
H. influenzae (and
bacterial soluble
cytoplasmic
fraction)
Gram-negative
bacteria flagellin
Bordetella pertussis
H292, HM3
RNA
157, 158
H292
RNA
139
TNF-␣ converting enzyme (TACE)
mediated TGF␣ release3 EGFR
activation
Transcriptional upregulation: bacterial
LTA3PAFR3via G protein
3ADAM103release of EGF from HBEGF 3EGFR3Ras3MEK1/23NF␬B
Transcriptional upregulation:
TLR23MyD883TAK13NIK3IKK ␤/
␥3I␬B␣3NF␬B
H292
Both
243
H292,HM3
RNA
154
HeLa,
HMEEC-1,
HM3,
NHBE
HeLa,
HMEEC-1,
HM3,
NHBE
HM3, HeLa,
A549
RNA
121
RNA
121
RNA
295
Transcriptional upregulation:
TGF-␤3RI/II3Smad3/43NF␬B
5AC
Transcriptional upregulation:
TLR23MyD883p38 MAPK
5AC
Negatively regulated by
phosphoinositide 3-kinase3Akt
pathway
Transcriptional upregulation: flagellin
binds to asialoGM13ATP
release3autocrine/paracrine binding
to G protein-coupled P2Y2
receptor3PLC activation3inositol
trisphosphate production3intracellular
calcium mobilization3through calcium
binding protein3MEK1/23ERK1/23
transcription factor activation
Transcriptional upregulation
HM3, HeLa,
A549
RNA
295
HM3, H292
RNA
177
BEAS2B
RNA
17
Transcriptional upregulation: ATP
release3P2Y receptor3PLC3PKC3
p38 MAPK3NF␬B
HM3 H292
RNA
167
H292
RNA
155
H292
H292
RNA
RNA
26
139
Transcriptional upregulation: ERK and
p38 MAPK3MSK-1 3 CREB3CRE
TGF-␣3EGFR activation
H292, HNE
RNA
256
H292
Prt
Transcriptional upregulation: ERK and
p38/MAPK3COX23PGE2
H292
RNA
130
Regulation inhibited by RAR␣ antagonist
H292
RNA
139
Increased mRNA steady-state expression
Transcriptional upregulation: ERK and
p38/MAPK3MSK-13CREB3CRE
Increased mRNA steady-state expression
Transcriptional upregulation via ERKRSK1-CREB-CRE pathway
HNE, H292
H292
RNA
256
H292, HNE
H292
RNA
257
2
DsRNA
2
5AC
2
TNF-␣
2
Cytokines/chemokines/lipid mediators
5AC
2
5AC
5AC
Cytokine-activated
eosinophils
Interleukin (IL)-1␤
5AC
2
5AC
2
5AC
5AC
8
Expression increased by 30 min and
maintained for 24 h. Regulation
inhibited by PKC and tyrosine kinase
inhibitors
Posttranscriptional regulation
Regulation inhibited by RAR␣ antagonist
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S. aureus LTA
Transcriptional upregulation via Srcdependent
Ras3MEK1/23ERK1/23pp90rsk3NF␬B
Regulation inhibited by RAR␣ antagonist
265
MUCIN GENES AND GLYCOPROTEINS
TABLE
6—Continued
Agonist
IL-4
MUC Gene
IL-9
5AC
5B
5AC
5B
5AC
5B
5AC
IL-13
2, 5AC
5AC
5B
5AC
IL-5
Neutrophil defensins
PGE2, 15-HETE
5AC
5AC
5B
5AC
5B
Cell Line
RNA/Prt*
Reference Nos.
Decreased mRNA expression
NHBEALI
RNA
119
No effect
NHBEALI
RNA
45
No effect
NHBEALI
RNA
45
Increased mRNA expression
Transcriptional upregulation
Increased mRNA expression
No effect
H292, NHBE
H292
H292
NHBEALI
No effect
168
RNA
RNA
171
45
RNA
226
No effect
A549, H292,
Calu-3
NHBEALI
RNA
45
Decreased expression
Increased expression
HNE
HNE
RNA/Prt
RNA
IL-6 3 activates cell in
autocrine/paracrine fashion3ERK;
IL173JAK23IL-6 secreted
Increased mRNA expression
Increased mRNA expression
NHBEALI
RNA
45
H292, NHBE
RNA
1
H292
RNA
26
Regulation inhibited by RAR␣ antagonist
H292
RNA
139
Posttranscriptional regulation
Proteolytic activity required,
posttranscriptional regulation
ROS
NHBE
A549,
NHBEALI
A549,
NHBEALI
H292
H292
Both
RNA
77
291
Both
78
Both
RNA
135
51
HSG
Prt
H292
Both
266
H292
Both
244
H292
RNA
86
H292
H292
H292, NHBE
RNA
RNA
RNA
26
26
169
H292
Both
136, 265, 266
H292
RNA
203
H292
NHBEALI
RNA
RNA
203
47
Increased mRNA expression
No effect
128
128
Proteases
Neutrophil elastase
2
5AC
4
5AC
5AC
Human airway trypsin
5AC
5AC
Tissue kallikrein
2
5AC
TGF-␣3EGFR3MEK1/23ERK
Proteolytic activity required to release
amphiregulin 3EGFR activation
Increased mRNA expression
Proteolytic activity and EGFR activation
43
Pollutants/reactive oxygen species
Hydrogen peroxide
5AC
Cigarette/tobacco
smoke
Cigarette/tobacco
smoke
5AC
Acrolein
Residual oil fly ash
5AC
5AC
5B
5AC
Transactivation of
EGFR3MEK1/23ERK
TACE-mediated TGF-␣ release3EGFR
activation
Transcriptional upregulation: ROS3Srcdependent JNK activation 3JunD
3AP-1 and/or EGFR3Ras/RafMEK3ERK3Fra-23AP-1
Increased expression
No effect
Mediated via PKA, PKC, EGFR
activation, and G proteins
Cell surface receptor agonists
Epidermal growth
factor family of
ligands
5AC
2, 5AC
Uridine 5-triphosphate
5B
5AC, 5B
Augmented by TNF-␣-mediated
upregulation of EGFR surface
expression3ERK/MAPK
Transcriptional upregulation:
EGFR3Ras3Raf3ERK3Sp1
No effect
Pertussin toxin-sensitive G protein and
MEK1/2-MAPK dependent; PKC and
PLC independent
Description of human cell lines: A549, a lung carcinoma cell line; HeLa, cervical adenocarcinoma cell line; HNE, human nasal epithelial cells;
HSG, human SMG cells; H292, NCI-H292, a human pulmonary mucoepidermoid carcinoma cell line; NHBE, normal human bronchial or tracheal
epithelial cells grown on Transwell membranes on a collagen layer; NHBEALI, differentiated NHBE cells; HM3, colon carcinoma cell line; HMEEC-1,
human middle ear epithelial cell line. See text for other definitions. * Gene product evaluated is mRNA and/or protein (Prt).
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IL-6/IL-17
5AC
5B
5AC
2
8
5B
Mechanism
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MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
processes that lead to mucus overproduction in chronic
airway diseases.
Few studies on the downregulation of mucin genes
have been reported. The glucocorticoid dexamethasone
decreases the abundance of MUC2 and MUC5AC mRNA
in airway epithelial cell lines (122) and in rat primary
airway epithelial cells grown submerged and at ALI (173).
Interestingly, it has been shown that the decreased expression of Muc5ac mRNA in rat airway epithelial cells
does not always produce a concomitant decrease in synthesis or expression of Muc5ac mucin (173). Identifying
mechanisms that affect repression of mucin gene expression and/or mucin protein expression will be useful in
ultimately reverting mucus overproduction in airway diseases.
B. Transcriptional Regulation by Infectious
Mediators of Mucin Genes
Bacterial colonization and infection of the airways
are major pathological features of CF and COPD. These
infections are associated with increased mucin production and mucus hypersecretion, resulting in airway obstruction. Bacteria activate transcription of host defense
genes via activation of specific signal transduction cascades. Bacteria-induced upregulation of mucin genes is
now recognized as a primary innate defensive response in
Physiol Rev • VOL
mammalian airways (13). This hypothesis, initially advanced by Professor Carol Basbaum, has significantly
advanced our understanding of the signaling pathways
that regulate mucin gene expression.
P. aeuroginosa and S. aureus are the primary pathogenic bacteria found in the airways of CF patients, while
S. aureus and H. influenzae are common pathogens that
exacerbate bronchitis in patients with COPD. By-products
of these bacterial infections activate mitogen-activated
protein kinase (MAPK) pathways, which are important in
transmitting extracellular signals from the cell surface to
the nucleus to transcriptionally upregulate mucin genes
(Fig. 6). This has been well-demonstrated for the MUC2
and MUC5AC genes (Table 6). The MAPK pathway is one
example that culminates in activation of the transcription
factor, nuclear factor kappa B (NF␬B), which in turn
regulates mucin gene expression (Fig. 6). However, NF␬B
is not the only transcription factor that mediates mucin
gene expression, as SP1 and AP-1 also upregulate mucin
gene expression following exposure to inflammatory/immune response mediators (86, 203).
1. MUC2 gene regulation
A seminal study on mucin gene expression showed
that supernatant from P. aeuroginosa increases MUC2
mRNA steady-state expression in bronchial explants and
in airway and colon epithelial cell lines and that lipid A
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FIG. 6. Schematic of signal transduction pathways that regulate mucin gene
transcription. Cytokines and lipid components of Gram-positive bacteria (lipoteichoic acid, LTA) or Gram-negative
bacteria (lipopolysaccharide, LPS) bind
specific receptors on cell membranes,
which directly or indirectly activate one
or more MAPK pathways. Current data
indicate that pathways initiated by bacterial by-products converge at RAS (154) to
activate NF␬B upregulation of MUC2 or
MUC5AC. Additionally, Sp1 or AP1 transcription factors can also be activated to
upregulate MUC2 or MUC5AC genes (Table 6). Thus diverse mediators upregulate
mucin gene transcription, and high levels
of inflammatory/immune response mediators result in mucin overproduction.
MUCIN GENES AND GLYCOPROTEINS
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late flagellin-induced ERK-dependent and -independent
pathways have not yet been identified.
Respiratory viruses also induce mucin overproduction during infection and additionally trigger exacerbations in patients with asthma, bronchitis, or CF. Doublestranded (ds) RNA is a biologically active component of
many respiratory viruses, and synthetic ds RNA can upregulate MUC2 transcription in stably transfected colon
cancer cells. Like bacterial flagellin, ds RNA stimulates
the extracellular release of ATP and activation of G protein-coupled ATP receptors on cell surfaces, resulting in
stimulation of PLC. In the case of ds RNA, this induction
activates PKC leading to activation of NF␬B via the p38
MAPK, but not the c-Jun amino-terminal kinase JNK, pathway (167).
2. MUC5AC gene expression
Early studies on mucin gene regulation demonstrate
that Gram-negative bacterial lysates, in addition to upregulating MUC2 mRNA, also increase expression of
MUC5AC mRNA in bronchial explants from normal or CF
patients (66) and in epithelial cancer cell lines (156). This
is not surprising as MUC5AC, like MUC2, has several
putative NF␬B cis-elements in its promoter sequence. P.
aeuroginosa upregulates MUC5AC expression following
activation of the p42/44 MAPK pathway via an EGFR
signaling cascade (136), analogous to how Gram-positive
bacteria activate MUC2 expression (154). MUC5AC
mRNA expression is increased following EGF/EGFR ligand/receptor binding (see sect. IIIC) and subsequent activation of the MAPK cascade (265, 266).
Nontypeable H. influenzae also upregulates MUC5AC
transcription via activation of NF␬B, but does so via heatstable cytoplasmic proteins rather than bacterial lipid oligosaccharides. Additionally, H. influenzae activates several
signaling pathways through cytoplasmic proteins that may
either positively or negatively regulate p38 MAPK. Although
H. influenzae directly phosphorylates p38, it also activates
negative regulators of p38, phosphoinositide-3-kinase and
Akt, a serine-threonine kinase (295). The net result of these
signaling cascades is upregulation of MUC5AC expression.
Bacterial and viral interactions with host cells can
also trigger autocrine/paracrine nucleotide signaling,
which mediates host defense responses at both the
mucin secretory and gene expression levels. ATP upregulates MUC2 gene expression in cancer cell lines
(167, 177). UTP upregulates expression of MUC5AC
and MUC5B genes in differentiated NHBE cells, following activation of a MAPK pathway by a UTP-specific G
protein-coupled receptor (47).
Ligand-dependent activation of EGFR increases transcription of the MUC2 (154) and MUC5AC (265, 266)
genes. In addition to the above-mentioned studies demonstrating NF␬B-mediated regulation, other mediators
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transcriptionally upregulates MUC2 promoter activity by
a MAPK pathway (157). The lipid A component of LPS is
a potent activator of host defense responses following
binding to receptors on cell surfaces. Subsequent studies
showed that LPS increases MUC2 transcription by activation of c-Src-Ras-Raf-1, which leads to mitogen-activated
protein kinase kinase (MEK)1/2 activation and subsequent ERK1/2 phosphorylation. ERK1/2 phosphorylation
leads to activation of the 90-kDa ribosomal S6 kinase
(pp90rsk), resulting in NF␬B (p65/p50) binding to the
NF␬B cis-sequence at ⫺1452/⫺1436 of the MUC2 promoter. A second NF␬B/c-rel sequence at ⫺234/⫺220 nt is
not functional in LPS activation of MUC2 (158).
Gram-positive bacteria can also transcriptionally upregulate MUC2 gene expression as lipoteichoic acid
(LTA) in the S. aureus cell wall, another potent activator
of host defense responses, activates MUC2 gene expression (154). However, the signaling pathways activated by
LTA interactions at epithelial cell surfaces are different
from those activated by LPS, although both mediators can
use the Ras-MEK1/2-ERK1/2 pathway that results in activation of NF␬B. S. aureus-LTA binds to the platelet activating factor receptor (PAFR) resulting in G protein-mediated activation of ADAM10, a matrix metalloprotease.
ADAM10 releases membrane-bound heparin binding-epidermal growth factor (HB-EGF), which binds to the EGF
receptor (EGFR). HB-EGF activation of EGFR leads to
downstream Ras and MEK1/2 activation, resulting in
pp90rsk phosphorylation and activation of NF␬B (154).
H. influenzae regulates MUC2 transcription by activating transforming growth factor (TGF)-␤ receptor type
I/II, inducing Smad3/4 complex activation and downstream NF␬B activation. Alternatively, H. influenzae can
also bind to the toll-like receptor (TLR)2, and activate
MyD88, TAK1, NIK, and IKK␤␥. This signal cascade results in release of I␬B␣ from the NF␬B-I␬B␣ complex and
therefore NF␬B-mediated transcription of the MUC2 gene
(121).
Bacterial flagella also activate MUC2 gene expression, but through a different cell surface binding and
cellular signaling mechanism than LPS. P. aeuroginosa
flagellin, a major structural component of the bacterium
flagella, binds to the epithelial cell surface ganglioside,
ASGM1, causing release of ATP and subsequent activation
of P2Y, a G protein-coupled receptor, with downstream
activation of phospholipase C (PLC), formation of inositol
trisphosphate, and calcium mobilization. This triggers
MAPK signaling through phosphorylation of MEK1/2 and
ERK1/2, which results in increased MUC2 transcription
(177). As the MAPK pathway accounts for only half of the
flagellin-induced signaling, the authors hypothesized that
a postulated calcium binding protein activates MEK1/2 as
well as an ERK independent pathway, thereby leading to
increased MUC2 transcription. The cis-sequences on the
MUC2 promoter and the transcription factors that regu-
267
268
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
(TGF-␣, EGF, and TNF-␣) transcriptionally regulate
MUC2 and MUC5AC and do so via the Sp1 transcription
factor following activation of EGFR/Ras/RAF/ERK1/2
pathways. Functional investigations revealed that binding
of Sp1 to SP1 cis-elements within the MUC2 promoter
(nucleotides ⫺2627 to ⫺2097) and MUC5AC promoter
(nucleotides ⫺202 to ⫺1) contributes to the ability of the
aforementioned mediators to regulate mucin gene expression. In contrast to an earlier study (265), TNF-␣ does not
potentiate MUC5AC expression in the presence of EGFR
ligands in H292 cells in this study (203).
Many inflammatory/immune response mediators in
the airway secretions or sputum of patients with asthma,
COPD, or CF regulate mucin gene expression. These include cytokines, oxidants, and proteases, certain of which
have been shown to increase MUC gene expression by a
variety of signaling cascades in vitro in cancer cell lines or
differentiated NHBE cells (Fig. 6, Table 6). In the first
study of the effect of cytokines on mucin gene expression,
TNF-␣, the primary orchestrator of inflammatory responses, was shown to increase MUC2 mRNA steadystate expression in H292 cells (155). TNF-␣ also increases
the abundance of MUC5AC, but not of MUC5B, mRNA
and does so by increasing the stability of MUC5AC mRNA
at the posttranscriptional level (26). TNF-␣ also regulates
expression of MUC5AC at the transcriptional level (139,
256) by mechanisms similar to those observed by IL-1␤
(see below). NF␬B cis-sequences in the promoter region
of MUC5AC through which TNF-␣ upregulates MUC5AC
expression have recently been identified (188).
IL-1␤, an inflammatory mediator that is also expressed early in inflammation, induces MUC2 and
MUC5AC expression in H292 or normal human nasal
epithelial (NHNE) cells via MAPK activation of both
ERK1/2 and p38 pathways. Three downstream mechanisms have been identified so far. These are 1) activation
of cyclooxygenase-2 and prostaglandin E2 production
(130), 2) presence of an active retinoic acid receptor ␣
(139), and 3) signaling via the mitogen and stress-activated kinase 1 (MSK-1), with subsequent activation of the
cAMP response element-binding protein (256).
The non-TH2 cytokines IL-6 and IL-17 also increase
MUC5AC and MUC5B mRNA steady-state expression in
differentiated NHBE cells. IL-17 upregulates MUC5B expression through an IL-6 paracrine/autocrine loop mediated by ERK signaling via JAK2-dependent signaling (45).
The TH2/Th2 cytokines, which are found in inflammatory airways and prominent mediators of asthmatic
airway inflammation and central mediators of GCM in
murine models of allergic asthma (see sect. IIB5), are
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C. Transcriptional Regulation by Inflammatory/
Immune Response Mediators
reported to increase mucin gene expression in vivo. However, increased mucin gene expression may simply correlate with GCM as higher levels of steady-state mucin gene
expression in models of allergic asthma reflect the increased number of goblet cells, which endogenously express mucin genes. The question of whether specific cytokines regulate mucin genes needs to be evaluated for
each MUC/Muc gene of interest. Steady-state analyses of
mucin mRNA expression following exposure to TH2 cytokines has shown that neither IL-4 nor IL-13 upregulates
MUC5AC mRNA expression in human airway epithelial
cancer cell lines (226) or in differentiated NHBE cells
(45). Another study shows that IL-4 decreases MUC5AC
expression in differentiated NHBE cells (119). However,
the situation may be different for the murine Muc5ac
gene, as IL-13 has recently been reported to increase the
promoter activity of Muc5ac following transfection of a
Muc5ac promoter-luciferase plasmid into murine Clara
cells (74). The TH2 cytokines IL-5 and IL-9 do not alter
MUC5AC or MUC5B mRNA abundance in differentiated
NHBE cells (45). In contrast, IL-9 increases MUC5AC
expression in NHBE cells cultured under submerged conditions and transcriptionally upregulates MUC5AC expression in H292 cells (168). IL-9 also increases MUC2 and
MUC5AC mRNA steady-state expression in H292 cells and
in submerged NHBE cells (171). These conflicting results
may reflect differences in model systems or culture conditions. Pathways whereby IL-9 regulates mucin gene expression have not yet been reported.
Neutrophils are the predominant inflammatory cell in
the airways of patients with CF, chronic bronchitis, and in
acute, severe exacerbations of asthma. Neutrophilic products such as proteases and oxidants have been evaluated
for their role in regulating MUC gene expression. Neutrophil elastase, a serine protease, increases expression of at
least two major respiratory tract mucin genes, MUC5AC
(135, 291) and MUC4 (77). Neutrophil elastase can regulate MUC5AC by at least two different mechanisms: 1) NE
induces oxidant stress in A549 and NHBE cells (79) and
regulates MUC5AC, as well as MUC4 by a posttranscriptional mechanism, e.g., by prolonging mRNA half-life, as
briefly discussed in section IIID; and 2) NE releases TGF-␣
resulting in EGFR activation and transcriptional regulation of MUC5AC in H292 cells (135). Other airway proteases such as kallikrein (43) and human airway trypsin
(51) have recently been shown to also regulate MUC5AC
expression following EGFR activation.
Extensive investigations of mucin gene expression
have also focused on other intrinsic and extrinsic factors/
compounds. Reactive oxygen species, which can be released by airway inflammatory cells, also regulate
MUC5AC expression and do so by EGFR activation (266)
and by TNF-␣-converting enzyme (TACE) (243). Heavy
metal particulates in fuel oil combustion products, particularly vanadium, also upregulate MUC5AC expression in
MUCIN GENES AND GLYCOPROTEINS
D. Posttranscriptional Regulation of Mucin Genes
Inflammatory-associated genes activated during lung
inflammation, including TNF-␣, endothelial and inducible
nitric oxide synthase, and cyclooxygenase, can be regulated posttranscriptionally as well as transcriptionally (reviewed in Ref. 182). Several inflammatory mediators/
products have now been shown to regulate mucin genes
at the posttranscriptional level. TNF-␣ (26), NE (291), and
IL-8 (16) increase MUC5AC expression in human epithelial cells by increasing mRNA stability. 12-O-tetradecanoylphorbol-13-acetate or forskolin increases MUC2
mRNA levels by a posttranscriptional mechanism in an
intestinal epithelial cancer cell line, via PKC- or protein
kinase A-dependent signal transduction pathways, respectively (280). MUC4 is posttranslationally regulated by
TGF-␤ in rat mammary epithelial cells (210). While inflammatory/immune response mediators posttranscriptionally
regulate MUC genes and significantly amplify gene expression, the mechanism(s) whereby they do so, and the
relevance of these pathways in airway cells, remain to be
determined.
Physiol Rev • VOL
IV. SUMMARY AND FUTURE DIRECTIONS
Mucins are glycoproteins characterized by TR domains that are high in serine or threonine and proline. A
mucin protein backbone is encoded by a MUC gene, of
which 18 human MUC genes have been identified by
recombinant DNA technology over the last two decades.
A majority of the TR serine/threonine residues are Oglycosylated, resulting in mucins being ⬎50% carbohydrate by weight. Based on the primary structure of their
MUC protein backbones, mucins are classified either as
secretory or membrane-tethered. Standardization of nomenclature and molecular details on MUC genes and
MUC gene products will be facilitated by the development
of a website (www.mucin.org) wherein genomic and
cDNA sequences, as well as protein sequences validated
by peptide sequencing or by antibodies specific to MUC
protein backbones, have been assessed.
MUC-specific antibodies have proven useful for identifying mucin localization in epithelial tissues, cells, and
secretions and investigating mucin biosynthesis and secretion, as well as characterizing and semi-quantitating
mucin levels in secretions from healthy individuals and
those with diseases. They should likewise prove useful for
isolating individual mucins for studies on mucin glycosylation and function. A comprehensive analysis of O-glycan
structures isolated from mucins of known MUC protein
backbones will establish whether specific mucins undergo altered glycosylation in airway diseases. This may
occur in chronic airway diseases consequent to inflammation, while there may be an additional downstream
effect of mutant CFTR on mucin glycosylation in a genetic
disease like CF.
The concept that mucins have a role in mucosal
immunology in the airways continues to gain validity.
Both secretory and membrane-tethered mucins function
as part of the innate immune defensive and mucociliary
clearance systems that protect the airway epithelium
against pathogens and environmental agents. The secretory mucins MUC5AC and MUC5B are major components
of airway mucus from healthy airways and sputum from
patients with chronic airway diseases. At least 10 other
mucins are expressed at the mRNA level in lung epithelial
cells; future studies will determine whether these gene
products are also expressed at the protein level, and will
lead to studies on the functional roles of specific membrane-tethered and secreted mucins. However, reliable
quantitation and comparison of mucin levels in mucus
samples from healthy airways and sputum samples from
diseased airways remains a challenging problem encumbered by the difficulties in procuring and processing samples. Nevertheless, determining the identities of specific
mucin gene products in airway epithelial cells and secretions is a crucially important step for investigations into
the functional roles of specific mucins in airway ho-
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airway epithelial cells (169). Acrolein, an aldehyde component of tobacco smoke, also increases MUC5AC expression (26). Tobacco smoke transcriptionally regulates
MUC5AC by two different mechanisms: 1) ROS activation
of EGFR via TACE-mediated release of amphiregulin or 2)
EGFR-independent Src-Jnk activation of JunD/Fra-2 binding to AP-1 cis-elements in promoters (86).
An EGFR signaling cascade is a common pathway by
which many stimuli, including oxidative stress, agarose
plug instillation, cigarette smoke, and NE, induce MUC2
(14) or MUC5AC (136) gene expression in vitro (Table 6).
The importance of this pathway in vivo is not fully established, as it requires expression of EGFR at the luminal
surface of goblet cells to activate the signaling mechanisms that increase MUC5AC expression. There is not
complete agreement on the expression and localization of
EGFR in the conducting airways. In one study, EGFR
immunoreactivity in healthy airways is rare and observed
only in goblet cells. EGFR expression is increased in
asthmatic airways and is detected in goblet and basal cells
(267). In other studies, EGFR expression in healthy airways is limited to the lateral junctions between columnar
epithelial cells and their junctions with basal cells and is
not observed on the luminal surfaces. EGFR expression is
increased in asthmatic airways and is localized to the
basolateral surface of pseudostratified columnar epithelium, except in areas of damaged epithelium, where
EGFR is found on the apical surfaces (207). EGFR
expression is also restricted to the basolateral aspect of
pseudostratified columnar epithelium in normal and CF
tissues (105, 289).
269
270
MARY CALLAGHAN ROSE AND JUDITH A. VOYNOW
Physiol Rev • VOL
mucins. Studies on biophysical and biological properties
of specific airway MUC mucins with defined O-glycan
chains are also important and will be facilitated when
adequate amounts of purified or recombinant MUC mucins are available. They will provide a basis for functional
studies delineating how specific domains in MUC protein
backbones, as well as in the attached O-glycans, contribute to and/or determine the biological and biophysical
properties of mucin glycoproteins that impact on the role
of mucins in mucosal immunology and thus on airway
health and disease. The ultimate goal of research in this
area of lung cell biology is to better understand airway
health to diminish the morbidity and mortality so intimately associated with chronic airway diseases (whether
inherited or acquired). Such information should facilitate
the development of early detection methods for airway
obstruction by mucus and of more efficacious pharmacological agents.
ACKNOWLEDGMENTS
We thank Dr. Bernard Fischer (Tables 4 and 6), Susan Nasr
(Tables 2 and 3), Alan Watson (Figs. 1, 5, and 6; Table 4), Charles
Kovach (Figs. 2 and 3), and Sami Mufarrij (Table 1) for their
invaluable contributions to the tables and figures. We also thank
Dr. Tracey Nickola, Susan Nasr, and Charles Kovach for critical
editing of manuscript drafts and Dr. Inka Brockhausen for editing the mucin glycosylation section. The authors recognize that
numerous investigators have contributed to the greatly expanded knowledge in this area of lung biology. We apologize for
omissions or errors.
Address for reprint requests and other correspondence:
M. C. Rose, Center for Genetic Medicine Research, Rm. 5700,
Children’s National Medical Center, 111 Michigan Ave. NW,
Washington, DC 20010 (e-mail: [email protected]).
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