Am J Physiol Lung Cell Mol Physiol 290: L622–L645, 2006;
doi:10.1152/ajplung.00477.2005.
Invited Review
NF-␬B activation as a pathological mechanism of septic shock
and inflammation
Shu Fang Liu and Asrar B. Malik
Division of Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center,
The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York;
and Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois
nuclear factor-␬B; septic pathophysiology; cytokines; signal transduction
SEPSIS AND ITS SEQUELAE, septic shock, acute respiratory distress
syndrome, and multiple organ dysfunction/injury (MOD/I),
represent a continuum of a syndrome encompassing multiple
pathological processes including systemic inflammation, coagulopathy, hemodynamic abnormalities, and MOD/I. Despite
decades of efforts and significant advance in supporting therapies, sepsis and septic shock remain the leading cause of death
amongst critically ill patients (156, 202). A major factor
contributing to the high morbidity and high mortality of septic
shock is the lack of the effective treatment (202). A better
understanding of the molecular mechanisms of sepsis and
septic shock may help to identify novel targets for the development of therapeutic strategy.
Septic shock is a systemic inflammatory response syndrome
(SIRS) to infection. It is now generally accepted that it is not
the infection itself but, rather, the host response to infection
that determines the outcome of sepsis (48). Bacterial pathogens
and their products trigger the inflammatory response by transcriptional activation of inflammatory genes, leading to the
release of large number of inflammatory mediators, including
cytokines, chemokines, adhesion molecules, reactive oxygen
Address for reprint requests and other correspondence: S. F. Liu, Div. of
Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center,
270-05 76th Ave., Research Bldg, RM B371, New Hyde Park, NY 11040
(e-mail: [email protected]).
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species (ROS), and reactive nitrogen species (RNS). Although
these mediators are important for host defense against invading
bacteria, they frequently cause SIRS and septic shock when
their production is uncontrolled and excessive. Simultaneously, anti-inflammatory pathways are also activated, leading to the release of anti-inflammatory cytokines, including
interleukin (IL)-4, IL-10, IL-13, IL-1 receptor antagonist,
transforming growth factor (TGF)-␤, and suppressor of cytokine signal inhibitor-1, that serve as counterregulatory mechanisms to dampen the inflammatory response. However, the
predominance of the inflammatory response, in combination
with a repressed anti-inflammatory mechanisms (262), results
in an imbalance between the two sets of counter mechanisms,
leading to the development of septic shock and septic MOD/I.
Thus septic shock is a result of exaggerated systemic inflammatory response to infection, and inflammatory mediators are
major determinants of septic phenotype.
Bacterial pathogens activate cytokine networks by induction of
multiple proinflammatory genes. This process is mediated by the
activation of inducible transcription factors, such as activating
protein-1 (AP-1) and nuclear factor (NF)-␬B. NF-␬B proteins
play pivotal roles in immune and inflammatory responses. Recent
studies on animal models of septic shock have demonstrated a
critical role of NF-␬B in the pathophysiology of sepsis.
In this review, we will summarize the current research on
NF-␬B and its regulatory mechanisms with emphasis on their
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Liu, Shu Fang, and Asrar B. Malik. NF-␬B activation as a pathological
mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol
290: L622–L645, 2006; doi:10.1152/ajplung.00477.2005.—The pathophysiology
of sepsis and septic shock involves complex cytokine and inflammatory mediator
networks. NF-␬B activation is a central event leading to the activation of these
networks. The role of NF-␬B in septic pathophysiology and the signal transduction
pathways leading to NF-␬B activation during sepsis have been an area of intensive
investigation. NF-␬B is activated by a variety of pathogens known to cause septic
shock syndrome. NF-␬B activity is markedly increased in every organ studied, both
in animal models of septic shock and in human subjects with sepsis. Greater levels
of NF-␬B activity are associated with a higher rate of mortality and worse clinical
outcome. NF-␬B mediates the transcription of exceptional large number of genes,
the products of which are known to play important roles in septic pathophysiology.
Mice deficient in those NF-␬B-dependent genes are resistant to the development of
septic shock and to septic lethality. More importantly, blockade of NF-␬B pathway
corrects septic abnormalities. Inhibition of NF-␬B activation restores systemic
hypotension, ameliorates septic myocardial dysfunction and vascular derangement,
inhibits multiple proinflammatory gene expression, diminishes intravascular coagulation, reduces tissue neutrophil influx, and prevents microvascular endothelial
leakage. Inhibition of NF-␬B activation prevents multiple organ injury and improves survival in rodent models of septic shock. Thus NF-␬B activation plays a
central role in the pathophysiology of septic shock.
Invited Review
NF-␬B IN SEPTIC PATHOPHYSIOLOGY
pertinence to inflammation and septic shock. We will review
the current knowledge about the role of NF-␬B and NF-␬B
pathways in septic pathophysiology. To better understand the
role of NF-␬B activation in septic MOD/I, we will also discuss
the biological functions of NF-␬B in a wide spectrum of
physiological and pathophysiological processes.
DESCRIPTION
AJP-Lung Cell Mol Physiol • VOL
as a transcriptional activator, whereas the RelA/RelB heterodimer represses the transcription of those genes (155).
Distinctive properties of different NF-␬B dimers increase the
ability of NF-␬B dimer to differentially regulate gene expression.
I␬B family of proteins. NF-␬B activities are regulated by the
I␬B family of proteins, which include I␬B␣, I␬B␤, I␬B␥,
I␬B⑀, I␬B␨, Bcl-3, p105 (NF-␬B1), p100 (NF-␬B2), and
MAIL (molecule possessing ankyrin-repeats induced by lipopolysaccharide). p105 and p100 have similar structural organization, containing p50 or p52 structure at their NH2 termini
and I␬B structure at their COOH termini (119, 169, 225). The
central portion of both proteins contains a glycine-rich region
that plays a critical role in processing of the precursors (169).
In resting cells, p105 and p100 are partially processed, generating p50 and p52, although the exact mechanisms of this
limited processing event is unknown. It is also unclear how and
why the proteasome-mediated proteolysis selectively degrades
the COOH-terminal portion of p105 and p100 but leaves an
intact NH2 terminus (p50 and p52). I␬B␥ is structurally the
COOH-terminal half of p105 protein but is translated from a
separately initiated mRNA (226). The two newly discovered
I␬Bs, I␬B␨ and MAIL, functionally differ from other I␬B
proteins (see later discussion), although the COOH-terminal
portion of these two proteins share high sequence homology
with other members of I␬B proteins (124, 259). A common
structure for all I␬Bs is the six to eight copies of ankyrin
repeats, called ankyrin repeat domain (ARD), which mediate
I␬B binding to the NF-␬B dimers, masking the nuclear localization sequence on NF-␬B proteins.
I␬B proteins are different in their structures, preference for
binding of NF-␬B dimers, biological functions, and modes of
activation. I␬B␣, I␬B␤, and I␬B⑀, but not other I␬Bs, have an
NH2-terminal regulatory domain, which is required for stimulation-induced I␬B degradation (226). Whereas I␬B␣ and
I␬B␤ preferentially interact with dimeric complexes containing
the transactivating subunits (RelA, RelB, and C-Rel), particularly those containing RelA (12, 226), I␬B␥ and I␬B␨ have a
preference for p50-containing dimers (169, 259). I␬B␣ effectively dissociates any prebound NF-␬B complex containing
ReA, RelB, or C-Rel from their cognate DNA sites, but it is
ineffective in promoting the dissociation of DNA-bound p50/
p52 homodimer (226). I␬B␥ interacts stably with p50/p65
dimer but not p65/p65 or C-Rel/C-Rel dimer (169). I␬B␨
preferentially associates with p50 rather than p65 and inhibits
the DNA binding of the p50/p65 heterodimer as well as the
p50/p50 homodimer (259). I␬B⑀ is exclusively found to be
associated with RelA and C-Rel (11). Whereas p105 is preferentially associated with p50-containing dimers (169), p100 is
associated with RelB-containing dimers (25). The cytoplasmic
retention of RelB-containing NF-␬B dimers is mediated exclusively by p100. There are also differences in the mechanism of
regulating I␬B gene expression. I␬B␣, I␬B␤, and I␬B⑀ are
constitutively expressed (119), but I␬B␨ and MAIL are induced by lipopolysaccharide (LPS) and proinflammatory cytokines (67, 259). I␬B␣, I␬B␤, and I␬B⑀ are ubiquitously expressed, whereas I␬B␥ is expressed only in certain cell types,
such as pre-B cells (108). I␬B␣, I␬B␨, and MAIL are NF-␬Bregulated genes (67, 110, 119), but the gene expression of
I␬B␤ is not regulated by NF-␬B (119). I␬B proteins respond
differently to NF-␬B activators. I␬B␤ only responds to a
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NF-␬B family of proteins. NF-␬B is a group of structurally
related transcriptional proteins that form dimers composed of
various combinations of members of the NF-␬B/Rel family
proteins. NF-␬B proteins in mammalian cells include NF-␬B1
(p50/p105), NF-␬B2 (p52/p100), RelA (p65), RelB, and C-Rel
(83, 119, 226). Except for a truncated form of RelA, RelA
(p37), seen in cells overexpressing proto-oncogene c-Myc (37),
no new NF-␬B protein has been reported since the first description by Sen and Baltimore (213) of NF-␬B as a B cell
nuclear factor binding to a site in the immunoglobin ␬ enhancer. The NF-␬B family of proteins is characterized by the
presence of a highly conserved 300-amino acid Rel homology
domain (RHD) composed of two immunoglobulin-like structures. RHD is responsible for dimerization, DNA binding, and
association with their inhibitory proteins, I␬Bs (119, 225). One
structural difference between RelB and RelA (or C-Rel) is that
RelB protein contains an NH2-terminus-activating domain
(225), which may explain the difference in its regulation.
NF-␬B1 (p50) and NF-␬B2 (p52) are synthesized as their
precursors, p105 and p100, which contain multiple copies of
the ankyrin repeat at their COOH termini, a structural characteristic of all I␬B proteins (1, 119, 225). p105 and p100 can
serve as p50 and p52 precursors as well as regulatory proteins.
Limited proteolysis of p105 or p100 protein at its COOH
terminus yields p50 or p52 protein. This proteolytic degradation of p105 and p100 is accelerated under inflammatory
conditions, which is one mechanism regulating the inducible
NF-␬B activation. Interaction between members of NF-␬B
family of proteins forms an NF-␬B dimer of distinct composition, which reflects variation in stimuli, cell types, or signal
transduction pathways (12, 119, 226). Those NF-␬B dimers
can be homodimers or heterodimers, although the most predominant form of NF-␬B is the p50/p65 heterodimer. Different
forms of the NF-␬B dimer exhibit distinct properties in term of
DNA binding preference, selectivity of interaction with I␬B
isoforms, and transcriptional capability. The RelA/C-Rel dimer
binds to the sequence of 5⬘-HGGARNYYCC-3⬘, whereas the
p50/p65 dimer preferentially binds to the sequence of 5⬘GGGRNNYYCC-3⬘ (12). The RelB/p52 dimer preferentially
recognizes a novel NF-␬B-binding sequence of 5⬘-GGGAGATTTG-3, which is not recognized by the RelA/p50
dimer (24). RelA-containing NF-␬B dimers preferentially interact with I␬B␣ and I␬B␤ (12, 226), whereas p50-containing
dimers have a preference for I␬B␥ and I␬B␨ (169, 259). NF-␬B
proteins are constitutively expressed in all cell types with the
exception of RelB, the expression of which is restricted to
lymphoid tissues (34). Although most NF-␬B dimers are activators of transcription, p52/p52 (83), p50/p50, and p65/p65
homodimers are transcriptional repressors. The homodimer of
p50 or p65 forms a complex with histone deacetylase
(HDAC)-1, binds to DNA, and suppresses NF-␬B-dependent
gene expression (267). The RelB/p50 or RelB/p52 dimer acts
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unable to shuttle between nucleus and cytoplasm and stay in
the cytoplasm (83). Moreover, I␬B␤ in the ternary complex is
resistant to phosphorylation and degradation by most signals,
preventing NF-␬B activation (44). I␬B␥/NF-␬B or p105/
NF-␬B complexes are also cytoplasmic, although only the NLS
on p50 is masked (169). One explanation for its cytoplasmic
retention is that I␬B␥/NF-␬B (or p105/NF-␬B) complex interacts with a cytoplasmic protein, leading to its docking or
masking of the NLS on p65 (169). I␬B␨ is located in nucleus,
where it negatively regulates NF-␬B DNA binding and inhibits
NF-␬B-mediated gene transcription (259).
REGULATION OF NF-␬B ACTIVITIES
Mechanisms regulating NF-␬B activity. NF-␬B is known to
be activated by ⬃460 activators (with more becoming known
every week), including physical stress, chemical stress, oxidant
stress, environmental stress, physiological stress, mitogens,
modified proteins, receptor ligands, physiological and pathological mediators, apoptotic mediators, bacteria and their products, fungi and their products, viruses and their products,
parasites and their products, proinflammatory cytokines, and a
variety of pathological conditions. The signal transduction
pathways leading to NF-␬B activation are multiple and complex. Some signaling pathways appear to link to a particular
stimulus, whereas other pathways are shared by multiple stimuli. One complexity in understanding the NF-␬B signaling
pathways is that a single stimulus can activate NF-␬B through
multiple signaling pathways, and multiple signaling cascades
that lead to NF-␬B activation can utilize a given signaling
component. One example for the former is LPS, which causes
NF-␬B activation by activating multiple signaling pathways
(Fig. 2). Examples for the latter are mitogen-activated protein
(MAP) kinase and protein kinase C (PKC) pathways, both of
which are involved in multiple signaling processes that lead to
NF-␬B activation. The signaling pathways that lead to NF-␬B
activation involve an extremely large number of signaling
molecules, particularly kinases, and a detailed description of
those molecules is beyond the scope of this review.
Although the upstream signaling pathways that lead to
NF-␬B activation are presented to be complex, those signaling
pathways converge at certain nodal points. There are both
canonical and noncanonical pathways of NF-␬B activation.
Some NF-␬B activators act principally through the canonical
pathways, whereas others act mainly through noncanonical
pathways (193). There are also NF-␬B stimulators that act
through both pathways. For the canonical pathways, the converging point is I␬B kinase (IKK) complex. NF-␬B activators
activate various signal transduction pathways that ultimately
result in the activation of IKK, which in turn causes the rapid
phosphorylation of I␬B proteins, on Ser32 and 36 for I␬B␣
(119) and Ser19 and 23 on I␬B␤ (94). Upon phosphorylation
by IKKs, I␬B proteins are recognized by E3RSIKB/␤-TrCP, the
receptor subunit of the Skp1-Cullin1-Roc1-F-box (SCF) ubiquitin ligase complex, which consequently results in polyubiquitination of I␬Bs (at Lys21 and 22 for I␬B␣) by the SCF
family of ubiquitin ligase (119). The ubiquitinized I␬B protein
is subsequently degraded by 26S proteasome system. I␬B
degradation exposes the NLS on NF-␬B protein, leading to the
translocation of the NF-␬B dimer into nucleus, where it binds
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subgroup of NF-␬B activators. I␬B␤ protein degradation is
observed following LPS or IL-1 stimulation, but it is not seen
following TNF-␣ or phorbol myristate acetate (PMA) stimulation (239). In contrast, all of these stimuli cause I␬B␣
degradation (239). Studies using I␬B␤ knock-in mice, in which
the I␬B␣ gene is replaced by the I␬B␤ gene, have confirmed
the divergent properties of I␬B␣ and I␬B␤. These studies show
that LPS causes both I␬B␣ and I␬B␤ degradation, but ischemia-reperfusion (I/R) only causes I␬B␣ degradation (71). Unlike I␬B␣, I␬B␤ is only partially degraded in response to most
extracellular signals (44). I␬B␤ forms an I␬B␤/NF-␬B/Ras
complex, which blocks the induced I␬B␤ phosphorylation and
degradation (44). Although both I␬B␨ and MAIL are inducible
proteins, I␬B␨ is induced by LPS and IL-1 but not by TNF-␣
(259), but MAIL is induced by all three stimuli (12). In contrast
to most I␬B proteins that are constitutively expressed cytoplasmic proteins, I␬B␨ and MAIL are inducible nuclear proteins
(124, 259). Contrasting sharply with the function of other I␬Bs,
MAIL serves as a transcriptional enhancer, enhancing LPSinduced IL-6 expression by ⬎20-fold (124). I␬B␣, I␬B␤, and
I␬B⑀ have different biological functions. I␬B␣ appears to
function as a strong negative feedback mechanism that allows
a fast turn-off of the NF-␬B response, whereas I␬B␤ and I␬B⑀
function to reduce systemic oscillation and stabilize the NF-␬B
response during longer stimulation (97).
I␬Bs inhibit NF-␬B activation through three mechanisms, by
sequestrating NF-␬B dimers in the cytoplasm, facilitating dissociation of DNA-bound NF-␬B dimers from their DNA binding sites, and exporting NF-␬B dimers from nucleus. NF-␬B
activation increases the expression and synthesis of I␬B␣ and
I␬B␨, which bind to NF-␬B dimers in the nucleus, thereby
enhancing their dissociation from DNA and causing their
export to cytoplasm by means of nuclear exportation mechanisms (83). Each member I␬B protein appears to employ
different mechanisms for their cytoplasmic retention of NF-␬B
dimers. Formation of I␬B␣/NF-␬B complex masks the nuclear
localization sequences (NLS) on p65, not that on p50, resulting
in a partial blockage of nuclear entry of NF-␬B dimers. Some
of the I␬B␣/NF-␬B complexes are able to enter the nucleus due
to the unmasked NLS on p50. However, those I␬B␣/NF-␬B
complexes entering the nucleus are actively transported back to
cytoplasm by means of the nuclear export sequences (NES) on
I␬B␣ (83). The nuclear import and export of I␬B␣/NF-␬B
complexes are continuous processes. The default location for
NF-␬B dimers is the cytoplasm because the effect of the NES
is dominant over that of the NLS (83). This nuclear import and
export mechanism is also responsible for the newly synthesized
I␬B␣ to dissociate activated NF-␬B dimers from DNA and
export them from nucleus (83). I␬B⑀ causes cytoplasmic distribution of NF-␬B dimers through mechanisms similar to that
of I␬B␣ (94). Nuclear import of the p50/p65 heterodimer (or
p50/p50 homodimer) is mediated by importin-␣3 and, to a
lesser extent, by importin-␣4 (69). NLS on p65 or p50 binds
directly to the NLS binding site of importin-␣3, leading to
nuclear translocation of the NF-␬B dimers (69). Binding of
I␬B␤ to NF-␬B dimers masks the NLS of one NF-␬B subunit
with the NLS on the other subunit being exposed (169).
However, the I␬B␤/NF-␬B complex interacts with a Ras-like
G protein, ␬B-Ras, to form a new I␬B␤/NF-␬B/␬B-Ras complex, which effectively masks the NLS on the other NF-␬B
subunit (44). Consequently, the I␬B␤/NF-␬B complexes are
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NF-␬B IN SEPTIC PATHOPHYSIOLOGY
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to its consensus sequence on the promoter or enhancer regions
of NF-␬B-regulated genes, resulting in gene transcription (Fig. 1).
NF-␬B activity is regulated by p100 and p105. Upon stimulation with cytokines such as TNF-␣, p105 is rapidly phosphorylated by IKKs on Ser927 and 932 in its proline, glutamic
acid, serine, and threonine rich region (94). Both IKK␣ and
IKK␤ play critical roles in p105 phosphorylation (94). The
death domain of p105 protein acts as a docking site for IKK
and facilitates an efficient Ser927 phosphorylation (15). p105
phosphorylation generates a binding site for ␤-TrCP, the receptor subunit of the SCF ubiquitin ligase complex, leading to
AJP-Lung Cell Mol Physiol • VOL
ubiquitination and subsequent degradation of p105 protein by
a proteasome system (12, 119). This releases the associated
NF-␬B dimer, which translocates into the nucleus and regulates its target gene transcription (Fig. 1). The p105 phosphorylation and degradation processes are facilitated by molecular
cross talk with glycogen synthase kinase-3␤ (GSK-3␤) (57)
and are inhibited by docking of p50 subunit to the ARD (49).
Upon stimulation, p100 is also subjected to the processes of
phosphorylation, ubiquitination, and proteasomal degradation,
resulting in the release and nuclear translocation of p52containing NF-␬B dimer (25). This p100 processing is tightly
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Fig. 1. NF-␬B activation cascade in the canonical pathways. Various NF-␬B activators, including inflammatory and stress stimuli, activate I␬B kinase (IKK),
which phosphorylates I␬B␣, leading to its recognition and ubiquitinization by the SCF family of ubiquitin ligase. This then targets I␬B␣ protein for rapid
degradation by 26S proteasome. I␬B␣ degradation exposes the nuclear localization sequence on NF-␬B proteins, resulting in its translocation to nucleus where
it binds to its consensus sequence in the promoter or enhancer regions of NF-␬B target genes. Upon stimulation, p105 and p100 are subjected to similar
phosphorylation, ubiquitination, and proteasomal degradation processes, resulting the release and nuclear translocation of p50- or p52-containing dimers and
transcription of NF-␬B target genes. The inducible p100 processing is preferentially induced by lymphokine-␤ (LT-␤) and other B cell activation signals, and
requires NF-␬B-inducing kinase (NIK) activity. The IKK that phosphorylates p100 appears to be IKK␣ homodimer. NF-␬B activity is regulated by additional
regulatory mechanisms including phosphorylation, acetylation, S-nitrosylation and S-glutathionylation of NF-␬B proteins. p65 phosphorylation or acetylation
increases, and p65 dedphosphorylation or deacetylation decreases NF-␬B activity. S-nitrosylation of p65 reduces NF-␬B activity. NF-␬B activity is also regulated
by synergistic or antagonistic interactions with other transcription proteins and by positive or negative feedback mechanisms (see text for detail). ATF, activating
transcription factor-2; BAFF-R, B cell-activating factor belonging to the TNF family receptor; CREB, cAMP response element binding protein; CBP, CREB
binding protein; C/EBP␤, CCAAT/enhancer-binding protein-␤; DA, deacetylation; IKK␣, -␤, -␥, I␬B kinase-␣, -␤, -␥; HMG, high mobility group; IRF,
interferon regulatory factor-1; JunD, jun protein D; NF-AT, nuclear factor of activated T cell; Oxy, S-glutathionylation; PPAR, peroxisome proliferator-activated
receptor; SCF, Skp1-Cul1-Roc1-F-box ubiquitin ligase complex; S-NO, S-nitrosylation; STAT6, signal transducer and activator of transcription 6; TR,
transcription; A, acetylation; P, phosphate; U, ubiqutinization.
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embryo fibroblasts deficient in IKK␣ and IKK␤ genes demonstrated that the chemotherapeutic agent doxorubicin induces
proteasome-dependent I␬B␣ degradation and subsequent
NF-␬B activation in the absence of IKK␣ and IKK␤ activities
and I␬B␣ Ser32 and Ser36 phosphorylation (94). Hepatitis C
virus protein 5A induces NF-␬B activation through tyrosine
phosphorylation of I␬B␣ at Tyr42 and Tyr305 and I␬B␣
degradation. However, I␬B␣ degradation is not mediated by a
proteasome, but rather by the protease calpain (248). Mitochondrial stress-induced NF-␬B activation involves the inactivation of I␬B␤ through calcineurin-mediated dephosphorylation, which is independent of IKK␣ and IKK␤ (21). NF-␬B
activity is regulated by posttranslational modification of I␬B␣
through mechanisms other than I␬B␣ phosphorylation. Taurine
chloramine inhibits NF-␬B activation by oxidizing I␬B␣ protein at Met45 (116). Transglutaminase 2 induces NF-␬B activation without stimulating I␬B␣ phosphorylation and degradation, but by inducing I␬B␣ polymerization. The polymerization results in NF-␬B dissociation and translocation into
nucleus where it regulates gene expression (136).
In addition to nuclear translocation as discussed above,
NF-␬B activity is controlled by additional regulatory mechanisms. These include regulation of nuclear import and export
of NF-␬B dimers, regulation of the recruitment of NF-␬B
dimer to the promoter or enhancer sites of NF-␬B target genes,
regulation of NF-␬B transcriptional activity after recruitment,
and positive or negative feedback mechanisms. It is reported
that low intracellular zinc reduces nuclear import of activated
NF-␬B dimers and inhibits the transcription of NF-␬B-driven
genes in human neuroblastoma cells (151). Increase in intracellular [Ca2⫹] accelerates NF-␬B dimer nuclear translocation
and promotes NF-␬B-mediated transcription (125). Commensal anaerobic gut bacteria, Bacteroides thetaiotaomicron, selectively antagonize virulent salmonella-induced NF-␬B activation by enhancing nuclear export of NF-␬B dimers (121).
This nuclear export does not utilize the traditional chromosomal region maintenance-1 (CRM-1)-dependent nuclear export mechanism but relies on a novel mechanism involving a
Bacteroides-induced association between p65 and the nuclear
hormone receptor peroxisome proliferator-activated receptor
(PPAR)-␥. Subsequently, the p65/PPAR␥ complex is exported
from nucleus, resulting in the attenuation of NF-␬B activation
(121). This mechanism provides a valid explanation how gut
commensal bacteria regulate inflammation.
Regulation of the recruitment of NF-␬B dimer to its target
genes and regulation of NF-␬B-mediated transcriptional activity are primarily mediated by two mechanisms, posttranslational modification of NF-␬B proteins and synergistic (or
antagonistic) interactions between NF-␬B and other transcription proteins, as well as transcriptional coactivators or corepressors. NF-␬B and chromatin interaction is also a critical
determinant of NF-␬B-mediated transcription (171). NF-␬B
proteins, particularly p65, are subjected to a variety of posttranslational modifications, including phosphorylation (83),
acetylation (41), S-nitrosylation (201), and S-glutathionylation
(190). NF-␬B protein phosphorylation has emerged as an
important mechanism regulating NF-␬B activity and NF-␬Bmediated gene transcription. Both p50 and p65 are phosphorylated by protein kinase A (PKA), resulting in increased DNA
binding activity (83, 101). However, p65 phosphorylation is a
better-characterized event. A variety of stimuli cause p65
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regulated and involves multiple functional regions of p100
protein. With the help of the COOH-terminal death domain, the
COOH-terminal ARD interacts with its NH2-terminal dimerization domain and NLS, thereby bringing the COOH- and
NH2-terminal sequences together to form a three-dimensional
domain, which is required for the inducible processing of p100
protein (198). The inducible p100 processing requires NF-␬Binducing kinase (NIK) and its downstream kinase IKK␣ activity but does not require IKK␤ and IKK␥, two key components
of the classic IKK complex (25). This suggests that the IKK
mediating the activation of the p100 NF-␬B pathway is an
IKK␣/IKK␣ homodimer complexed directly with NIK. Consistently, the p100-processing based NF-␬B activation pathway
is not activated by typical NF-␬B inducers such as LPS,
TNF-␣, IL-1␤, and dsRNA, but it is rather activated by signals
involved in B cell maturation and lymphoid organogenesis,
including lymphotoxin-␤-receptor activation, engagement of
BAFF-R (B cell-activating factor belonging to the TNF family
receptor) or CD40 ligand (25). Activation of the IKK␣/p100/
NF-␬B pathway causes the expression of a subset of NF-␬Bdependent genes such as organogenic chemokine genes that
regulate B cell maturation, B cell function, and lymphoid
organogenesis and maintenance of secondary lymphoid organs
(25). This p100 processing-based NF-␬B pathway has been
referred to as noncanonical or alternative NF-␬B pathway in
the literature to distinguish it from the classic IKK/I␬B␣/
NF-␬B pathway (Fig. 1). However, the cascade of events
leading to the activation of the p100/NF-␬B pathway are
identical to that responsible for the activation of the IKK/I␬B␣/
NF-␬B pathway. Activation of both pathways is subjected to
the process of phosphorylation, ubiquitination, and proteasomal degradation. It is argued that the p100 NF-␬B pathway
should be classified as part of the canonical pathway to distinguish it from true noncanonical pathways that will be discussed
below.
Noncanonical pathways are signaling pathways leading to
NF-␬B activation without involving molecular events such as
IKK activation, I␬B␣ serine phosphorylation, or I␬B␣ degradation by the ubiquitin proteasome system (193). Noncanonical pathways are divergent signaling pathways without a clear
converging point. Hypoxia induces NF-␬B activation without
causing I␬B␣ serine phosphorylation and I␬B␣ degradation,
but rather it causes I␬B␣ phosphorylation at Tyr42 (119). The
subsequent release of NF-␬B dimer from the tyrosine-phosphorylated I␬B␣ is suggested to be mediated by interaction
with phosphoinositide-3 kinase (119). Hypoxia-reoxygenation
or pervanadate treatment-induced NF-␬B activation is mediated by c-Src-dependent tyrosine phosphorylation of I␬B␣, but
it is independent of IKK activation (70). Hypoxia-reoxygenation also activates p56/Lck tyrosine kinase, which causes
NF-␬B activation by tyrosine phosphorylation of I␬B␣ (152).
Hydrogen peroxide (H2O2) activates NF-␬B through a combination of Syk tyrosine kinase-mediated tyrosine phosphorylation of I␬B␣ and serine phosphorylation of p65 (235). UV
radiation-induced NF-␬B activation requires 26S proteasomemediated I␬B␣ degradation (119) but is independent of IKK
activity and I␬B␣ Ser32, Ser36, or Tyr42 phosphorylation (94,
119). The UV radiation-induced NF-␬B activation depends on
I␬B␣ phosphorylation at a cluster of COOH-terminal sites by
casein kinase II (CKII) (94). H2O2 induces NF-␬B activation
without causing I␬B␣ degradation (30). Studies on mouse
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NF-␬B IN SEPTIC PATHOPHYSIOLOGY
AJP-Lung Cell Mol Physiol • VOL
transferase, CBP/p300, is the major acetyltransferase, and
HDAC3 is the major deacetylase, mediating NF-␬B acetylation/deacetylation (41). Acetylation of p50 enhances its activity (80). The effect of p65 acetylation on its activity depends on
the site of acetylation. Acetylation at Lys221 enhances p65
DNA binding, impairs its assembly with I-␬B␣, and reduces
NF-␬B dimer nuclear exportation, resulting increased NF-␬B
activity (42). Deacetylation of p65 protein by HDAC3 promotes its binding to I␬B, leading to rapid nuclear exportation
of the deacetylated NF-␬B complex through a CRM-1-dependent mechanism (41). This p65 deacetylation is believed to be
an important mechanism in terminating NF-␬B response. Consequently, the cytoplasmic pool of latent I␬B/NF-␬B complexes is replenished. This readies the cells for the next
NF-␬B-mediated response. This reversible p65 acetylation also
acts as a molecular switch that controls the duration of NF-␬B
transcriptional activity. Acetylation and deacetylation are key
mechanisms regulating chromatin remodeling, which can alter
NF-␬B transcription activity by affecting their recruitment to
target promoters.
NF-␬B activity is also regulated by S-nitrosylation (56, 201)
and glutathionylation (174, 190). S-nitrosylation inhibits
NF-␬B activation at several steps in the NF-␬B activation
cascade. S-nitrosylation inhibits IKK␤ activation (201), stabilizes I␬B protein, protecting it from degradation, and inhibits
NF-␬B binding and transcriptional activities (56). S-glutathionylation of p50 protein is responsible for redox-mediated
regulation of NF-␬B activity (190). The Cys62 of p50 is highly
oxidized in the cytoplasm and strongly reduced in the nucleus.
The reduced Cys62 is essential for the DNA binding of
p50-containing NF-␬B dimer (174).
NF-␬B proteins interact with large number of transcriptional
proteins either through a direct physical interaction or through
interaction with a third protein, resulting in an altered NF-␬B
activity and NF-␬B-mediated transcription. This interaction
can be either synergistic or antagonistic and can be either
reciprocal or nonreciprocal. Interaction between NF-␬B and
JunD (90), CREB (223), CCAAT/enhancer-binding protein-␤
(C/EBP␤, also called NF-IL6) (147, 186), interferon (IFN)
regulatory factor-1 (IRF-1) (251), Kruppel-like factor 5 (4),
POU-domain transcription factor-2 (Oct-2) (214), and nuclear
factor of activated T cell (147) is synergistic and reciprocal,
leading to augmented transcription activities mediated by both
NF-␬B and other transcription factors. Interaction between
NF-␬B and activating transcription factor-2 (20), breast cancer
gene 1 (17), high mobility group box 1 (3), Notch (66), really
interesting new gene (RING) finger protein, AO7 (10), promoter selective transcription factor 1 (142), signal transducer
and activator of transcription 6 (STAT6) (222), and transcription factor IIB (254) is synergistic but unreciprocal, leading to
the augmentation or facilitation of NF-␬B-mediated transcription without affecting the transcriptional activity mediated by
the partner proteins. NF-␬B binds to positive transcription
elongation factor-b to stimulate transcriptional elongation by
RNA polymerase II (14). Interactions between NF-␬B and
STAT1 (81), E2F transcription factor 1 (43), mammalian
transcriptional repressor RBP-J (CBF1) (178), IFN-inducible
p202a protein (150), forkhead box P3 (Foxp3) (19), and zincfinger protein ZAS3 (99) are antagonistic and unreciprocal,
inhibiting NF-␬B-mediated transcription without affecting the
transcriptional activity of the partner proteins. On other hand,
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phosphorylation (83). Phosphorylation of p65/p50 heterodimer
by PKA enhances its DNA binding activity (83). Cells from
mice deficient in serine/threonine protein kinase, GSK-3␤, and
NF-␬B-activating kinase (NAK, also known as TBK or T2K)
showed normal NF-␬B activation in response to a variety of
NF-␬B inducers when measured by I␬B degradation, NF-␬B
nuclear translocation, and binding to DNA. However, in both
cells, NF-␬B was unable to drive gene transcription, suggesting
that NF-␬B protein phosphorylation by these two kinases plays
a critical role in regulating NF-␬B transactivating activity (83).
The phosphatidylinositol 3-kinase (PI3K)/Akt-mediated RelA
phosphorylation plays an important role in gram-negative enteric bacteria-induced NF-␬B activation (91). Numerous kinases cause p65 protein phosphorylation and enhance NF-␬B
transactivation activity. Some of them such as PKA (83), PKC␨
(94), CKII (36, 83), GSK-3␤ (27), and TNF receptor-associated factor (TRAF) family member-associated NF-␬B activator-binding kinase 1 (TBK1) (28) act directly on p65 protein,
whereas others including NIK (83) and PI3K/Akt (83, 232) act
indirectly by activating IKK␣, which in turn phosphorylates
p65. All three IKKs, IKK␣, IKK␤, and IKK⑀, phosphorylate
p65 at Ser536 (28). Phosphatase 2A (260) and phosphatase 4
(263) dephosphorylate p65 protein. Regardless of the phosphoacceptor sites, p65 serine phosphorylation, in majority of
the cases, enhances NF-␬B transcriptional activity. GSK-3␤
phosphorylates p65 at Ser468, resulting in reduced basal p65
activity (27). However, GSK-3␤-mediated p65 serine phosphorylation appears to affect inducible NF-␬B activity differently. Cells from mice deficient in the GSK-3␤ gene showed
impaired NF-␬B-mediated transcription in response to a variety of NF-␬B inducers (83). p65 threonine dephosphorylation
increases NF-␬B activity (263), implying that p65 threonine
phosphorylation decreases NF-␬B activity. The mechanisms
underlying the enhancement of NF-␬B transcriptional activity
by p65 serine phosphorylation have also been investigated. It is
believed that the COOH-terminal region of nonphosphorylated
p65 interacts with RHD, thereby interfering with both DNA
and cAMP response element binding protein (CREB) binding
protein (CBP)/p300 binding. Phosphorylation of p65 at Ser276
by PKA prevents this intramolecular association, thereby facilitating its DNA binding and interaction with the transcriptional coactivator CBP/p300, enhancing NF-␬B transcriptional
activity (83). However, it remains unknown whether the same
mechanism is applicable to other kinases-induced p65 phosphorylation. Kinases causing p65 protein phosphorylation are
multiple and diverse. These kinases do not act on the same
phosphor-acceptor sites. PKA and CKII phosphorylate p65 at
Ser276 and Ser529, respectively (36, 83), whereas PKC␨
phosphorylates p65 at Ser311 (94). IKK␣, which mediates the
effects of NIK and PI3K/Akt, phosphorylates p65 at Ser536
(83, 113), whereas IKK␤, which does not mediate the effects
of NIK and PI3K, also phosphorylates p65 at Ser536 (94). It
has been reported that differential p65 phosphorylation modulates NF-␬B transcriptional activity in a cis-acting element and
promoter-specific context, thus leading to a phosphorylation
state-dependent gene expression profile (7).
Reversible acetylation of NF-␬B protein serves as another
mechanism regulating NF-␬B activity. Both p50 and p65
subunits can be acetylated at multiple lysine residues, and this
acetylation plays an important role in the regulation of NF-␬B
activity in vivo (41, 80). The transcriptional coactivator/acetyl-
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and 48 kDa, respectively, the large size of the IKK complex
indicates the presence of additional components, including I␬B
and NF-␬B proteins as well as upstream kinases. Because IKK
is the converging point for multiple and divergent signal
pathways, it is likely that the upstream kinase in the IKK
complex varies with signaling pathway involved. Although
IKK␣ and IKK␤ display similar activity in vitro (119), studies
using IKK␣ or IKK␤ knockout mice or transgenic mice overexpressing the inactivatable variant IKK␣ have revealed distinct functions for the two catalytic subunits (83, 119). IKK␤
mediates I␬B phosphorylation and degradation, NF-␬B nuclear
translocation, and NF-␬B-dependent gene transcription in response to inflammatory mediators and cytokines, whereas
IKK␣ is largely dispensable for this response (83, 119). In
response to cytokines and inflammatory mediators, IKK␣ contributes to NF-␬B-mediated gene transcription by its nucleosomal function. IKK␣ phosphorylates p65 protein (94) and
causes gene-specific phosphorylation (6) and subsequent acetylation of histone H3 (258), promoting the recruitment of
NF-␬B dimer and enhancing the transcription of NF-␬B-regulated genes. IKK␣ mediates p100 protein processing and the
activation of p100-dependent pathway that has been discussed
in detail above (25, 94). The IKK␤-dependent pathway mediates the activation of innate immunity and inflammatory responses (25), whereas the IKK␣-dependent pathway is involved in the termination and resolution of inflammatory responses (133). The IKK␣-dependent pathway suppresses
inflammatory response by accelerating RelA and c-Rel protein
turnover as well as their removal from promoter of proinflammatory genes (133).
Phosphorylation is an essential step toward IKK activation.
Phosphorylation at Ser177 and 181 of the IKK␤ activation loop
or Ser176 of the IKK␣ activation loop is required for IKK
activation (119). This phosphorylation can be achieved either
by the action of an upstream kinase or by an autophosphorylation caused by IKK itself. It is proposed that upstream
signaling events induce a proximity mechanism in which the
activator contacts each IKK/IKK dimer, increasing their proximity within the higher-order IKK complex and thereby facilitating mutual transautophosphorylation of IKK (83). IKK
phosphorylation increases (78, 83, 192, 227, 233), and IKK
dephosphorylation by protein phosphatase-2C␤ decreases its
activity (194). Numerous kinases are known to phosphorylate
and activate IKK, but none has proven to be specific IKK
kinase. These kinases include NIK (94), NAK (83), NAKassociated protein 1 (78), MAP/ERK kinase kinase-1
(MEKK1) (119), MEKK3 (94), TGF-␤-activating kinase-1
(TAK1) (227), TBK1 (192), and PKC␤ (233). Activation of
these kinases by various signaling pathways results in IKK
phosphorylation and activation and the subsequent NF-␬B
activation. It is reported that TNF-␣- and IL-1␣-induced
MEKK3 activation results in the formation of an IKK/I␬B␣/
NF-␬B complex, which regulates rapid NF-␬B activation,
whereas activation of MEKK2 results in the assembly of an
IKK/I␬B␤/NF-␬B complex, which controls the delayed NF-␬B
activation (210).
IKK has functions other than phosphorylating I␬Bs. Both
IKK␣ and I␬B␤ phosphorylate ␤-catenin. IKK␣ increases,
whereas IKK␤ decreases, ␤-catenin-dependent gene transcription (129). IKK␥ has nuclear function and shuttles into the
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interaction between NF-␬B and PTEN (phosphatase and tensin
homolog deleted on chromosome ten) or estrogen receptor is
antagonistic and reciprocal, resulting in a mutual inhibition of
the transcriptional activity mediated by both proteins (68, 88,
242). Reciprocally negative cross talk between NF-␬B and
AP-1 has also been reported (123), although positive cross talk
between those two proteins is more likely (90). NF-␬B activity
and NF-␬B-mediated transcription are inhibited by interactions
with its negative regulators, protein inhibitor of activated
STAT1 (143) and zinc finger protein A20 (94). NF-␬B interacts with various transcriptional coactivators and co-repressors, and a dynamic balance between these coactivators and
co-repressors regulates NF-␬B-mediated transcription (82).
NF-␬B activity is influenced by intranuclear p65 protein
abundance and stability, which are also actively regulated. The
p65 protein is subjected to a Pin1-dependent prolyl isomerization and ubiquitination-mediated proteasomal degradation.
Prolyl isomerization enhances NF-␬B activity by inhibiting
p65 binding to I␬B␣, resulting in an increased nuclear accumulation and stability of p65 protein (205). Proteasome-mediated proteolysis of p65 protein reduces its nuclear concentration and, thus, NF-␬B activity (205). Intranuclear proteasome
can degrade DNA-bound p65 protein, which not only promotes
the termination of NF-␬B-mediated transcription and response
but also reduces intranuclear p65 abundance (206). This accelerated p65 degradation is believed to be a mechanism of
inflammation termination and resolution (133).
NF-␬B activity is regulated by positive and negative feedback mechanisms. It is reported that RelA increases I␬B␣
phosphorylation and degradation, which serves as a positive
feedback loop for high-affinity NF-␬B complexes (261).
NF-␬B activation stimulates its upstream kinases (59), which
also form positive feedback. NF-␬B also activates several
negative feedback mechanisms. NF-␬B activation increases
I␬B␣, I␬B␨, or MAIL (119, 67, 110), which in turn inhibits
NF-␬B activation (172). NF-␬B activation upregulates the
expression of NF-␬B negative regulators, twist-1, twist-2
(231), and p65-interacting inhibitor of NF-␬B, SINK (253),
which interact directly with NF-␬B protein and inhibits its
transcription activity. NF-␬B also activates negative regulators
of upstream signal molecules, resulting in an inhibition of
NF-␬B signaling (185).
IKK. The key step leading to NF-␬B activation in the
canonical pathways is the activation of IKK. IKK is a large
protein complex with a kinase core composed of three subunits: IKK␣ (IKK1), IKK␤ (IKK2), and IKK␥ [also called
NF-␬B essential modulator, NEMO or IKK associated protein,
IKKAP] (119). IKK␣ and KK␤ are the catalytic subunits, and
IKK␥ is the regulatory subunit. IKK␥ associates with IKK␣/
KK␤ dimer formed between the two catalytic subunits via their
leucine zipper motifs to assemble a large IKK holocomplex.
This complex assembly is essential for stimulus-dependent
IKK activation. IKK␥ lacks catalytic domain, but it is essential
for IKK activation. It serves an important regulatory function
by connecting IKK␣/KK␤ dimer to upstream signaling molecules. IKK␣ and KK␤ share 52% overall sequence identity and
65% identity in their catalytic domains, and IKK␥ is not
structurally related to the catalytic subunits (119). Depending
on the isolation procedure, IKK complex has been reported to
be 700 –900 kDa as revealed by gel filtration analysis. Because
the molecular masses of IKK␣, IKK␤, and IKK␥ are 85, 87,
Invited Review
NF-␬B IN SEPTIC PATHOPHYSIOLOGY
BIOLOGICAL FUNCTIONS
Regulation of cell proliferation and apoptosis. NF-␬B participates in a variety of cellular activities and plays important
roles in diverse biological functions. The two most prominent
and well-defined functions for NF-␬B are regulation of immunological and inflammatory responses and regulation of cell
proliferation and apoptosis. In normal cells, NF-␬B proteins
are generally antiapoptotic and are regulators of cellular survival pathways. Activation of NF-␬B mediates the expression
of multiple antiapoptotic or cell survival genes, including bfl-1
(Bcl-2-related genes from a human fetal liver) (61), receptor
for activated C kinase-1 (46), inhibitors of apoptosis-1 and -2
(IAP-1 and IAP-2) (224), X chromosome-linked inhibitor of
apoptosis protein (141), cellular Fas-associated death domainlike IL-1␤-converting enzyme (FLICE) inhibitory protein
(162), inhibitor of caspase 8 (224), and survivin (224). NF-␬B
promotes survival during mitotic cell cycle arrest (165). Inhibition of NF-␬B pathway by various means promotes apoptosis
(249). Activation of the NF-␬B pathway suppresses putative
proapoptotic and tumor repressor genes such as PTEN and p53
(54, 242). This inhibition is reciprocal, because these two
proapoptotic proteins also inhibit NF-␬B activity (54, 88).
Tumor suppressors PTEN and p53 and the proapoptotic protein
Fas-associated factor-1 exert their antitumor or proapoptotic
action by negatively regulating NF-␬B activity and NF-␬Bmediated gene transcription (54, 88, 187). The importance of
NF-␬B in cell proliferation and embryonic development is
further evidenced by studies on NF-␬B or IKK knockout mice.
Mice deficient in p65 or IKK␤ and mice deficient in both p50
and p65 died at embryonic day 12.5–14.5 due to massive
apoptosis (12, 139). IKK␣-deficient mice lack limbs, tails, and
rears and exhibit severe deformities in craniofacial and several
other organs (119). In tumor cells, however, NF-␬B appears to
have dual functions, acting as both tumor promoter and tumor
suppressor. Numerous lines of evidence support the notion that
NF-␬B promotes tumorigenesis and tumor progression. A
constitutive NF-␬B activity is detected in most tumor cell lines
but is rarely detectable in normal cells (224). Increased NF-␬B
activity is also detected in various cancer tissues (224). Inhibition of NF-␬B activity in those tumor cells suppresses their
proliferation, leading to apoptosis (224). NF-␬B proteins are
oncogenic. Several putative oncogenes induce cellular transformation though activation of the NF-␬B pathway (224).
AJP-Lung Cell Mol Physiol • VOL
NF-␬B mediates the expression of multiple genes that are
associated with tumor cell growth and survival and plays an
essential role in every step of tumorigenesis and tumor progression (224). NF-␬B activation promotes tumor cell proliferation and migration and mediates tumor invasion and metastasis (224). NF-␬B activation also plays important role in
angiogenesis (224), which is critical for solid tumor growth.
NF-␬B activity is essential for tumor maintenance and for
cancer cell resistance to chemotherapies or TNF-␣ therapy
(224). In recent years, evidence has also emerged showing that
NF-␬B activation mediates apoptosis (224). NF-␬B mediates
the expression of several proapoptotic genes including Fas
ligand and c-Myc (224). NF-␬B has been reported to mediate
p53 tumor repressor gene expression (224) and to stabilize p53
protein (77), although another report has demonstrated that
NF-␬B inhibits p53 transcription (54). NF-␬B activity is required for the induction of apoptosis in several cell lines in
response to various apoptosis inducers (224). Human melanoma cells are protected against UV-induced apoptosis by
downregulation of NF-␬B activity and Fas expression (224).
Activators of NF-␬B induce apoptosis, and inhibitors of
NF-␬B inhibit apoptosis (224). Blockade of NF-␬B pathway
predisposes and triggers tumor formation in the skin (224).
These two opposite sets of data are not necessarily contradictory. They may represent a timely switch from one response to
another in adaptation to changes in cellular environment. It has
been reported that NF-␬B can be either proapoptotic or antiapoptotic, depending on the timing of NF-␬B activity being modulated relative to the death insult (224). Elucidation of the
molecular mechanisms underlying this timely switch may help
to better understand the biological basis of tumorigenesis and
to identify better targets for tumor prevention.
Regulation of immunological and inflammatory responses.
NF-␬B pathway plays a central role in the immune and inflammatory responses. The important roles of NF-␬B in adaptive
immunity are evidenced by demonstrations that mice deficient
in NF-␬B proteins develop a variety of immunological deficiencies. Mice lacking NF-␬B1 (p50/p105) exhibit an impaired
B cell proliferation, antibody secretion, and defects in B
cell-mediated immune response (12 139). Mice deficient in
NF-␬B2 (p52/p100) show defects in B cell maturation and T
cell activation (12 139). The RelA (p65) knockout mice display
embryonic lethality due to massive apoptosis in the liver (12
139). RelB knockout mice show defects in hematopoiesis,
reduced antigen-presenting dendritic cells in the thymus, impaired cellular immunity, as well as multifocal and mixed
infiltration of inflammatory cells in several tissues (12 139).
C-Rel null mice exhibit defective B cell and T cell proliferation, defective immunoglobin production, and T cell-dependent immune response (12 139). NF-␬B1 and NF-␬B2 double
knockout mice lack mature B cells and osteoblasts (12 139).
NF-␬B1 and RelB double knockout mice died postnatally due
to immune deficiencies (12 139). Mice deficient in I␬B proteins also develop various forms of immune deficiencies (12,
139).
Regulation of adaptive immunity includes regulation of
immune cell generation and activities. NF-␬B proteins are
actively involved in those regulations. NF-␬B activity is critically required for hematopoiesis and for the differentiation and
maturation of both myeloid and lymphoid immune cells, including T lymphocytes, B lymphocytes, natural killing cells,
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nucleus where it competes with p65 for binding to CBP,
leading to a repression of NF-␬B-mediated transcription (243).
I␬B kinase-⑀ (IKK⑀ or IKKi) is a structural homolog of
IKK␣ and IKK␤. LPS, TNF-␣, IL-1, and IL-6 induce IKK⑀
activity. Overexpression of IKK⑀/IKKi causes I␬B␣ phosphorylation at Ser32 and Ser36 and stimulates NF-␬B activity
(189). However, dominant negative mutant of IKK⑀/IKKi has
no effect on TNF-␣- or IL-1-induced NF-␬B activation, although it blocks NF-␬B activation induced by PMA and T-cell
receptor activation (189). Cells lacking the IKK⑀/IKKi gene
show normal activation of the canonical NF-␬B pathway,
suggesting that it is not essential for this pathway (94). IKK⑀/
IKKi plays a pivotal role in integrating inflammatory signals
into a coordinated activation of IRF-3 and NF-␬B (94) as well
as coordinated activation of NF-␬B and C/EBP␤ or C/EBP␦
(73), augmenting the inflammatory response.
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lution phase of inflammation (134). The IKK␣ pathway contributes to the resolution of inflammation (133).
Roles in other physiological and pathological processes.
Inappropriate NF-␬B activation is one of the pathogenic mechanisms of a list of diseases, particularly those with inflammation or apoptosis as a component. In the nervous system,
NF-␬B activity increases by many folds in acute neurodegenerative disorders such as stroke, severe epileptic seizures, and
traumatic brain injury, and in chronic neurodegenerative conditions, including Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis (157). Depending on where it is activated, NF-␬B activation can be
deteriorative or protective. In general, activation of NF-␬B in
microglia promotes the development of neurodegenerative disorders, whereas NF-␬B activation in neurons protects them
against neuronal degeneration (157). Neuronal NF-␬B activation also provides neuroprotection against glutamate-induced
excitotoxicity (154). NF-␬B mediates glial cell activation,
which contributes to neuronal injury (157).
NF-␬B activity is developmentally regulated and is required
for normal neuronal development and functions (157). NF-␬B
participates in a differentiation program that triggers the progression of axon-associated Schwann cells into a myelinating
phenotype (160). Proper growth and elaboration of neural
processes are essential for the establishment of a functional
nervous system during development and are integral features of
neural plasticity throughout life. Inhibition of NF-␬B activity
with NF-␬B decoy ODN substantially reduces the size and
complexity of the neurite arbors of sensory neurons cultured
with brain-derived neurotrophic factor (89). NF-␬B is activated
in association with long-term potentiation (LTP) of synaptic
transmission, a process that is believed to be a cellular mechanism of learning and memory (157). Blockade of NF-␬B
activation reduces LTP and abolishes long-term depression of
synaptic transmission (157). Mice lacking p65 protein show a
selective learning deficit in the spatial version of the radial arm
maze (160).
NF-␬B serves as an integrator of diverse signaling pathways
that lead to myocardial disorders (114) and has been implicated
in the pathogenesis of multiple cardiovascular diseases. NF-␬B
is proatherogenic, and NF-␬B activation contributes significantly to the development of atherosclerosis (51, 114). NF-␬B
activity and the expression of NF-␬B target genes increase in
atherosclerotic lesions (51). Proatherogenic factors activate
NF-␬B, and suppression of NF-␬B activity prevents the development of atherosclerosis (51). NF-␬B plays an important role
in angiogenesis, vascular restenosis, and postinjury vascular
fibrosis (114). NF-␬B activation is involved in the pathogenesis of several other cardiovascular diseases or pathological
conditions, including transplant rejection (114), angina pectoris (114), I/R injury (114), myocardial infarction (114), autoimmune myocarditis (264), congestive heart failure (114),
dilated cardiomyopathy (114), and cardiomyocyte hypertrophy
(197). Ischemic preconditioning causes NF-␬B activation,
which provides protection against ischemia myocardial injury
induced by subsequent ischemia (114).
In the respiratory system, an increased NF-␬B activity contributes to the pathogenesis of multiple airway and lung diseases. NF-␬B activation is an integral part of the pathological
mechanisms of asthma and other chronic obstructive pulmonary diseases as well as cystic fibrosis (252). NF-␬B activation
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and dendritic cells (58, 225). NF-␬B also plays an essential role
in the production of a specialized subpopulation of immune
cells (65, 225). NF-␬B proteins are key mediators of immune
cell antiapoptotic signals and cell survival signals (225).
NF-␬B activity is critically required for the survival of T
lymphocytes, B lymphocytes, and dendritic cells (224, 225).
RelA, RelB, and NF-␬B2 are required for the development of
lymphoid organs (25). IKK activity is also essential for lymphocyte development, maturation, survival, and function (211,
225). Both IKK␣ and IKK␤ are required for mature T cell
generation and survival, and IKK␤ has an additional role in
regulatory and memory T cell development (211, 225).
NF-␬B is also a major regulator of immune cell functions. In
the Th1 response, induction of intrinsic NF-␬B activity is
required for postdifferentiation IFN-␥ production and clonal
expansion (53, 139). IL-12 production by human dendritic cells
also requires intrinsic NF-␬B activity (128). The switch of
immunoglobulin genes to secondary immunoglobulins is an
event critical for the generation of functional diversity of a
humoral immunity. NF-␬B family of proteins have important
functions in the regulation of isotype switching. Absence of
NF-␬B activity reduces the expression of certain germ-line CH
genes and impairs class switching and antibody secretion (58).
NF-␬B activity is also crucial to innate immunity. NF-␬B
activity is required for the development and maturation of all
hematopoietic cells including macrophages and neutrophils
(58, 224), which are at the front line of innate immunity.
NF-␬B activity is essential for these cells to exert their host
defense function against invaded bacterial pathogens. Inhibition of NF-␬B pathway or deletion of NF-␬B genes results in
defective host-defense function. Mice deficient in p50 display
a defective bacterial clearance capacity and increased susceptibility to Streptococcus pneumoniae and Listeria monocytogenes infections (216). Overexpression of I␬B␣ selectively in
the liver causes a defective bacterial clearance in liver and
increased susceptibility to L. monocytogenes infection, despite
having intact immunocytes and inflammatory cells (132). Inhibition of NF-␬B activation using p65 decoy oligodeoxynucleotides (ODN) also impairs bacterial clearance capacity of Staphylococcus aureus (85). Knockout of NF-␬B-dependent genes also impairs bacterial clearance capacity. TNF
receptor (TNFR) knockout mice show an impaired bacterial
clearance of Escherichia coli (166). ICAM-1 knockout mice
display a decreased clearance of Pseudomonas aeruginosa and
increased susceptibility to S. aureus infection (207). Interestingly, bacterial pathogen subverts macrophage’s host-defense
capability by disrupting the NF-␬B pathway (203). During
endotoxemia, LPS causes delayed neutrophil apoptosis, which
is abrogated by inhibiting NF-␬B activation, and NF-␬B inhibition accelerates neutrophil apoptosis (47).
Evidence supporting a pivotal role of NF-␬B activation in
inflammatory response is overwhelming. NF-␬B mediates the
expression of extremely large number of proinflammatory
genes, including cytokines, chemokines, immune receptors,
enzymes, and other proinflammatory molecules (11 183). An
increased NF-␬B activity is observed in virtually every form of
inflammation, and inhibiting NF-␬B activation prevents the
development of those pathological conditions. NF-␬B may also
play a role in inflammation resolution. However, it appears that
different NF-␬B subunits are involved in the onset and reso-
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stimulated insulin secretion in pancreatic beta cells requires
NF-␬B activity (175). NF-␬B is involved in the signaling
process that initiates parturition. Increased production of surfactant protein A near-term fetal lung causes the migration of
fetal amniotic fluid macrophages to the maternal uterus, where
they increase the production of IL-1␤ that activates NF-␬B,
leading to labor (52).
ROLE OF NF-␬B IN SEPTIC PATHOPHYSIOLOGY
Signaling pathways that lead to NF-␬B activation during
sepsis. Consistent with the concept that septic shock is a
clinical syndrome with diverse etiologies, NF-␬B is activated
by a variety of bacteria (Table 1), bacterial products (Table 2),
and proinflammatory cytokines released during sepsis (Table
3). NF-␬B is the final target of those septic shock inducers.
Bacteria and bacterial components trigger inflammatory response by binding to and activating their receptors, Toll-like
receptors (TLRs). TLRs are the mammalian homologs of the
Drosophila protein, Toll, which belongs to the Toll/IL-1 receptor (TIR) domain-containing superfamily of proteins. At
least 13 members of TLRs exist, and 10 of them (TLR1–
TLR10) have been identified in humans (241). All TLR subtypes contain an extracellular leucine-rich domain, which mediates the formation of TLR homodimers or heterodimers, and
a cytoplasmic TIR domain, which is essential for the assembly
Table 1. Bacteria that activate NF-␬B
Anaplasma phagocytophilum
Bacteroides forsythus
Bartonella henselae
Bordetella pertussis
Chlamydia pneumoniae
Chlamydia psittaci
Chlamydia trachomatis
Enteropathogenic Escherichia coli
Ehrlichia chaffeensis
Enteroinvasive Escherichia coli,
Fusobacterium nucleatum
Gardnerella vaginalis
Helicobacter pylori
Hemophilus influenzae
Haemophilus influenzae
Lactobacilli Lactobacillus
Listeria monocytogenes
Mycobacteria Mycobacterium
Mycobacterium tuberculosis
Mycoplasma fermentans
Neisseria gonorrhoeae
Neisseria meningitides
Porphyromonas gingivalis
Porphyromonas gingivalis
Prevotella intermedia
Prevotella intermedia
Pseudomonas aeruginosa
Rhodococcus equi
Rickettsia rickettsii
Salmonella Dublin
Salmonella typhimurium
Shigella flexneri
Staphylococcus aureus
Streptococci group A
Streptococci group B
Streptomyces californicus
Ureaplasma urealyticum
Yersinia enterocolitica
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mediates the development of various forms of acute lung injury
and acute respiratory distress syndrome induced by endotoxemia, hemorrhage, mechanical ventilation, allograft rejection,
bleomycin, and IgG immune complex deposition (72, 181, 204,
252, 266). NF-␬B activation is involved in the pathogenesis of
lung interstitial diseases such as sarcoidosis and asbestosis
(252). NF-␬B is activated by a variety of air pollutants and
contributes pulmonary inflammation induced by air pollution
(252).
In the gastrointestinal system, NF-␬B activation is both
injurious and protective. On one hand, NF-␬B activation plays
a role in gastric ulcer formation and contributes significantly to
pathogenesis of celiac disease (153), collagenous and ulcerative colitis, and Crohn disease (127). On the other hand,
NF-␬B promotes restitution of wounded intestinal epithelial
monolayers (63) and protects against radiation-induced intestinal epithelial cell death and intestinal injury (64). NF-␬B is
involved in multiple liver diseases in which deregulation of cell
apoptosis is the major mechanism (95). Inhibition of NF-␬B
activation protects mice from T cell-mediated liver injury (107)
and prolongs liver allograft survival (256).
In the kidney, NF-␬B activation plays a role in the pathogenesis of immune glomerulonephritis (148) and chronic
FK506 nephropathy (238). Inhibition of NF-␬B activation with
NF-␬B decoy ODN prevents postreperfusion inflammation in a
renal allograft model (245).
Activation of NF-␬B pathway mediates I/R injury in multiple organs, including brain (176), heart (114), lungs (204),
kidney (31), liver (13), and intestine (269). In general, NF-␬B
activation mediates I/R organ injury but protects cells from
I/R-induced apoptosis (164).
In the joint and skeletal muscle system, activation of the
NF-␬B pathway is involved in several physiological and pathological processes. Treadmill exercise results in a significant
increase in IKK and NF-␬B activities in skeletal muscle of rats,
suggesting that the NF-␬B pathway may play a role in exercise
adaptation (96). Mice subjected to 10 days of hindlimb unloading showed an increased NF-␬B activity, increased expression
of NF-␬B-regulated genes, and decreased soleus fiber crosssectional area (an indicator of muscle atrophy), all of which are
abrogated in p105/p50 knockout mice (105), suggesting that
NF-␬B activation is one of the mechanisms underlying skeletal
muscle disuse atrophy. Activation of NF-␬B by muscle-specific expression of activated IKK␤ transgene causes severe
muscle wasting (29) that resembles clinical cachexia, suggesting an important role of NF-␬B activation in muscle wasting
seen in several pathological conditions, including cancer, sepsis, denervation, and immobilization. NF-␬B-mediated muscle
wasting requires inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production, indicating that the NF-␬B
effect is mediated by an iNOS/NO pathway (60). Activation of
the NF-␬B pathway plays important role in the pathogenesis of
rheumatoid arthritis and other forms of arthritis (234).
A dysregulated NF-␬B contributes to the pathogenesis of
multiple inflammatory and proliferative skin disorders or diseases, including psoriasis, incontinentia pigmenti, sunburn,
Lyme disease, allergic contact dermatitis, and autoimmune
diseases, as well as skin cancer (16).
NF-␬B activation is involved in or contributes to the development of metabolic disorders such as obesity (8), insulin
resistance (8), and diabetes (130). It is reported that glucose-
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Table 2. Bacterial components and products
that activate NF-␬B
of downstream signaling complex. Different bacterium or bacterial components utilize different TLR subtype. For example,
mycobacterial products activate TLR1 (237), whereas Helicobacter pylori and Salmonella muenchen flagellin interact selectively with TLR5 (170). Peptidoglycan, a major component
of gram-positive bacteria, utilizes TLR2, whereas LPS, the
major component of gram-negative bacteria, utilizes TLR4
(26). TLR2 is also the primary receptor recognizing other
gram-positive bacteria cell components (26). ␤-Glucans, the
major structural component of Fungi, induce NF-␬B activation
without utilizing TLR4 (135). Thus bacteria and their components can activate NF-␬B through multiple and diverse signal
transduction pathways. Many of the pathways that lead to
NF-␬B activation have not been fully elucidated. The TLR4mediated LPS signaling pathways are better characterized and
are discussed in detail here (Fig. 2).
To initiate the signaling cascades, LPS first interacts with
LPS-binding protein, which facilitates its binding to its receptor, CD14. This results in the recruitment of the TLR4 homodimer to cell membrane to form a receptor complex (167
241). Another LPS-recognizing molecule, MD-2, is also an
important component of the receptor complex. A physical
association between MD-2 and TLR4 is crucial for LPS response (167). The molecular mechanisms underlying this receptor complex assembly remain incompletely understood. It is
suggested that transfer of LPS from CD14 to TLR4 is a
necessary step for TLR4 activation (167). Upon stimulation,
TLR4 recruits IL-1 receptor-associated kinase-1 (IRAK-1) and
IRAK-4 via interaction with myeloid differentiation factor 88
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Table 3. Cytokines that activate NF-␬B
Tumor necrosis factor-␣
Tumor necrosis factor-␤
Interferon-␤
Interferon-␥
Interleukin-1␣
Interleukin-1␤
Interleukin-1F6
Interleukin-1F8
Interleukin-1F9
Interleukin-2
Interleukin-3
Interleukin-6
Interleukin-8
Interleukin-12
Interleukin-15
Interleukin-17
Interleukin-18
Granulocyte/Macrophage colony-stimulating factor
Macrophage colony-stimulating factor
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Cholera toxin from Vibrio cholerae
Cytolysin from Vibrio vulnificus
Diphosphoryl lipid A from Rhodobacter sphaeroides
Enterotoxin A from Bacteroides fragilis
Enterotoxin A from Staphylococcus
Enterotoxin B from Staphylococcus
Flagellin from Pseudomonas aeruginosa
Flagellin from Salmonella muenchen
FliC (flagella filament protein) from Salmonella enteritidis
Flagella filament structural protein from Salmonella enteritidis
Fumonisin B1 from Fusarium verticillioides
G(Anh) M Tetra from Escherichia coli
Internalin B from Listeria monocytogenes
Leukotoxin from Pasteurella haemolytica
Lipotheichoic acid from gram-positive bacterial wall
Lipoteichoic acid from Listeria monocytogenes
Lipoarabinomannan from Mycobacterial cell wall
Lipopolysaccharide.
Lipoprotein from Bacteroides forsythus
Lipoprotein from Mycobacterium leprae
Porin IB from Neisseria gonorrhoeae
Lipoprotein from Mycoplasma fermentans
Lipoprotein from Mycoplasma fermentans
Mannoproteins from Cryptococcus neoformans
Membrane proteins from Mycoplasma penetrans
Muramyl peptides
Peptidoglycan from gram-positive and gram-negative bacteria
Peptidoglycan-polysaccharide from Streptococcus group A bacteria
Phospholipases from Listeria monocytogenes
Porins from Neisseria
Porins from gram-negative bacteria
Protein A from gram-positive bacteria
Toxic shock syndrome toxin-1 from Staphylococcus
(MyD88) family of adaptor proteins. MyD88 proteins harbor a
TIR domain at their NH2 terminus, which mediates their
conjugation to TLRs through a TIR/TIR interaction, and a
death domain at their COOH terminus, which interacts with the
death domain on IRAK-1/4, leading to the recruitment of
IRAK-1/4 to the TLR complex. Five members of Myb88
proteins have been identified: Myb88, TIRAP (TIR domaincontaining adaptor protein), TRIF (TIR domain-containing
adaptor molecule-inducing IFN-␤), TRIF-related adaptor molecule, and sterile ␣- and armadillo motif-containing protein
(241). Although Myb88 participates in multiple TLR signaling,
TIRAP is suggested to link only with TLR4 and TLR2 (257).
Different adaptor protein links to different downstream signaling molecules. The immediate downstream molecule for
MyD88 and TIRAP is TRAF-6. After TLR4 activation,
TRAF-6 is recruited to the TLR complex and activated by
IRAK-1 or IRAK-4, which are already in the receptor complex,
and bind to TRAF-6 via a TRAF domain (257). The IRAK-1or IRAK-4/TRAF-6 complex is then released from the receptor
complex and associated with TAK1 via TAK-binding proteins,
TAB1, TAB2, and TAB3 (109), which serve as a bridge by
physically linking TAK1 to TRAF-6. TRAF-6 contains a
RING domain ubiquitin ligase activity that facilitates the synthesis of lysine 63-linked polyubiquitin chains by autoubiquitination, a process that requires another protein, called the
TRAF-interacting protein with a forkhead-associated domain
(TIFA) (62). Interaction between these polyubiquitin chains on
TRAF6 and the zinc finger domain of TAB1, TAB2, or TAB3
leads to the formation TRAF-6-TAB1/2/3-TAK1 complex
(117). IRAK-1 is degraded, and the TRAF-6-TAB1/2/3-TAK1
complex moves into cytoplasm to form a large protein complex, whereby it induces TRAF6-mediated activation of TAK1.
This leads to the activation of IKK, resulting in the activation
of NF-␬B (257).
The downstream kinases for TRIF include TANK-binding
kinase-1 (TBK-1), TRAF-6, and IKK⑀/IKKi, which mediate
the MyD88-independent TLR4 signaling pathway (257). TRIF
mediates two distinct pathways. Linking of TRIF to TRAF-6
leads to the activation of the TAK1/IKK pathway as described
above. Linking of TRIF to TBK1 or IKK⑀/IKKi activates these
two kinases. TBK1 phosphorylates and activates IKKs directly,
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leading to NF-␬B activation (192), whereas IKK⑀/IKKi phosphorylates I␬B␣ (189), which leads to I␬B␣ degradation and
NF-␬B activation. IKK⑀/IKKi can also activate IKKs via
interaction with an interacting protein, TANK (38).
RIPs (RIP1, RIP2, RIP3, and RIP4) are a group of death
domain-containing serine/threonine kinases that mediate signal
transduction processes leading to NF-␬B activation. RIPs are
key signaling molecules for TNF-␣ receptor activation and
play a role in TLR signaling. In response to LPS, RIP1 is
associated to TLR4 via interaction with TRAF-2 or TRAF-6,
resulting in the activation of PI3K/Akt pathway (244). However, this pathway does not appear to play a major role in
AJP-Lung Cell Mol Physiol • VOL
LPS-induced NF-␬B activation. RIP1 is recruited to TLR3/
TRIF complex and mediates TRIF-induced NF-␬B activation
(94). Because TRIF is an essential signaling molecule for
TLR4, it is possible RIP1 interacts directly with TRIF to mediate
TLR4 signal. RIP2-deficient macrophages display an impaired
NF-␬B activation in response to LPS, and RIP2-deficient mice
are resistant to the lethal effect of LPS, indicating an important
role of RIP2 in LPS/TLR4 signaling (45). RIP4 mediates
NF-␬B activation induced by multiple stimuli, and dominant
negative versions of TRAF-1, TRAF-3, and TRAF-6 block this
activation, indicating that RIP4 mediates LPS-induced NF-␬B
activation via TNF signaling pathways (161).
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Fig. 2. TLR4 signaling pathways that lead to NF-␬B activation. Binding of LPS and other TLR agonists to the TLR4/CD14/MD-2 receptor complex activates
multiple intracellular signal cascades that involve the recruitment of downstream adaptor molecules and kinases, leading to activation of IKK and subsequent
activation of NF-␬B. The IKK complex is the point of convergence of these signaling pathways. TLR4 signaling also activates multiple kinases that phosphorylate
p65 directly, enhancing NF-␬B transcription activity. NF-␬B activation results in the expression of TNF-␣, which in turn activates multiple intracellular signal
cascades via interaction with TNF receptor 1 (TNFRI) complex, leading to the activation of IKK and NF-␬B. Signaling molecules participating in these signaling
processes are: LBP, LPS binding protein; TLR-4, Toll-like receptor 4; MyD88, myeloid differentiation factor 88; TIRAP, Toll/interleukin-1 receptor (TIR)
domain containing adaptor protein; TRIF, TIR domain containing adaptor molecule inducing interferon-␤; IRAK-1/4, IL-1 receptor-associated kinase-1/4;
TRAF-2/5/6, TNF receptor associated factor-2/5/6; TAK1, TGF-␤-activated kinase 1; TAB1/2/3, TAK-binding protein 1/2/3; TBK-1, TANK-binding kinase-1;
IKK⑀/IKKi, I␬B kinase-⑀/I␬B kinase i; TANK, TRAF family member-associated NF-␬B activator; TRADD, TNFRI-associated death domain protein; FAK, focal
adhesion kinase; RIP1/RIP2/RIP3/RIP4, receptor-interacting protein 1/2/3/4; ECSIT, evolutionarily conserved signaling intermediate in Toll pathways; MKK3/6,
mitogen-activated protein kinase kinase 3/6; p38, p38 mitogen-activated protein kinase; MEKK1/3, mitogen-activated protein kinase/ERK kinase kinases 1/3;
ERK, extracellular signal-regulated kinase; PKA, protein kinase A; PKC␣, protein kinase C␣; PKC␨, protein kinase C␨; PKR, protein kinase R; CKII, casein
kinase II; PI3K, phosphatidylinositol-3-kinase; Akt, protein kinase B; c-Src, c-Src tyrosine kinase; PI-PLC, phosphatidylinositol-specific phospholipase C.
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antisense oligonucleotides or cells from PKC-deficient mice
has demonstrated critical roles of these PKC isoforms in
mediating LPS-induced NF-␬B activation and NF-␬B-dependent gene transcription (35, 40, 94). However, it remains
unclear how specific PKC isoforms activate NF-␬B. PKC␨
phosphorylates p65 directly at Ser311, resulting an enhanced
NF-␬B activity (94). Upon activation with inflammatory stimuli, PKC␨ is associated with the IKK complex and causes I␬B␣
phosphorylation (208), suggesting that PKC␨ can also activate
IKK. Other PKC isoforms, such as PKC␤ (233), have also
been demonstrated to activate IKK directly upon B cell receptor activation. However, it is unknown whether it plays a role
in LPS signaling.
LPS activates PKA, CKII, and PI3K/Akt, which cause p65
phosphorylation either by direct interaction or by indirect
action through the activation of IKK␣, leading to increased
NF-␬B activity and NF-␬B-mediated gene transcription (36,
94, 232). PI3K/Akt is linked to upstream signaling molecules
IRAK1 by interacting with TRAF-6 and RIP (244).
LPS and other bacterial components trigger the release of
numerous inflammatory cytokines (Table 3), which contribute
significantly to septic pathophysiology. Those cytokines cause
NF-␬B activation through their respective signaling pathways.
The TNF signaling pathways are most well characterized and
described here. Upon stimulation, TNFRI recruits TNFR-associated death domain protein (TRADD) (94). TRADD is an
adaptor protein that binds to and recruits downstream adapters,
TRAF-2 or TRAF-5, to the receptor complex. TRAF-2 or
TRAF-5 subsequently recruits RIPs to the receptor complex by
direct TRAF/RIP interaction (94). Different RIP isoform interact with different bridging molecules. RIP1 interacts with
TRAF-2 (94), whereas RIP2 interacts specifically with
TRAF-1, TRAF-5, and TRAF-6, but not with TRAF-2,
TRAF-3, or TRAF-4 (158). Interaction between RIPs and
IKK␥ leads to the oligomerization of the IKK complex (94),
resulting in IKK activation, I␬B phosphorylation and degradation, and subsequent NF-␬B activation. Recent studies have
indicated that TNF signaling cascades are more complicated
than this simple module. First, the formation of a TNFRI/
TRAF-2/RIP complex and subsequent recruitment of IKK
require the participation of other interacting proteins or kinases. It has been reported that the focal adhesion kinase
(FAK) acts as bridge linking TRAF-2 to RIP. TNF-induced
TRAF-2/RIP interaction and the subsequent recruitment of
IKK complex are not observed in FAK⫺/⫺ cells (79). RIP is
not the only molecule linking TRAF-2 to IKK; NIK is also
reported to interact with TRAF-2 and activates IKK complex
(230). MEKK3 interacts with RIP and directly phosphorylates
IKK and is required for IKK activation (94). MEKK3 functions
downstream of RIP and TRAF-2 (94). In response to TNF-␣,
the MAP3K TAK1 binds to the TRAF-2 and IKK complex,
leading to the activation of IKK and NF-␬B pathway (94).
TAB2 and TAB3 are the adaptor proteins bridging TRAF-2
and TAK1 (109). In addition to the classic TNF signaling
cascades, TNF-␣ activates IKK/NF-␬B via PKC-dependent
c-Src kinase activation. Activation of PKC␣ by TNF-␣ leads to
the activation of tyrosine kinase, c-Src, which causes the
phosphorylation of IKK␤ at Tyr188 and Tyr199 near its
activation loop, resulting in NF-␬B activation and the expression of NF-␬B-dependent genes (104).
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Activation of TLR4 by LPS leads to the activation of all
three classic MAP kinase (MAPK) pathways, the Ras-RafMEK1/2-ERK1/2 pathway, the protein kinase R (PKR)MKK3/6-p38 pathway, and the MEKK1/4-MKK4/7-JNK
pathway (26). ERK activation has been reported to act as an
important temporal regulator of NF-␬B activation and NF-␬Bdependent gene expression in response to IL-1 (112). Specific
inhibitors of ERK-1/ERK-2, JNK, or p38 have been shown to
inhibit NF-␬B activation or to suppress the expressions of
NF-␬B-dependent genes (26, 76, 112). However, a direct
molecular link between these three MAPK pathways and
NF-␬B has not been fully established. The upstream signaling
molecules linking PKR [the MAP kinase kinase kinase
(MAP3K) for p38 pathway] to TLRs are the TRAF family of
adaptor proteins, TRAF-2 and TRAF-5 (84), but the downstream molecules linking p38 to NF-␬B remain to be elucidated. Kinases downstream to MAPKs are MAPK-activated
protein kinases (MKs). Activation of MAPK pathways can
cause NF-␬B activation by activating their downstream MKs.
The ribosomal S6 kinase-1 is a substrate of ERK1/ERK2 and
can physically interact with the IKK complex (184). The
mitogen- and stress-activated protein kinase-1, another downstream MKs of ERK1/ERK2, can associate with and phosphorylate p65 at Ser276, enhancing NF-␬B-mediated gene transcription (94).
Several MAP3Ks upstream of p38 and JNK, including NIK,
NAK, MEKK1, MEKK2, MEKK3, and Tpl2 have been demonstrated to directly phosphorylate and activate IKK (83, 94,
173), suggesting that LPS can induce NF-␬B activation by
activating those upstream kinases without involving the entire
signaling cascades of these three MAPK pathways. Activation
of TLR4 by LPS leads to MEKK1 activation, which in turn
causes IKK phosphorylation and NF-␬B activation (173).
MEKK1 is linked to TLR4 via its upstream signaling molecule,
TRAF-6, and via interaction with an adapter protein, ECSIT
(evolutionarily conserved signaling intermediate in Toll pathways) (94). MEKK3 mediates LPS- and TNF-induced NF-␬B
activation (94), although different upstream signaling molecules are involved. For LPS, the upstream signaling is transduce by TLR4/MyD88/IRAK/TRAF-6 cascade (103), whereas
for TNF, the upstream signaling molecule is RIP, which links
to TNFR via TRAFs, leading to MEKK3 activation and subsequent IKK phosphorylation and activation (94). Different
MEKK isoforms play different biological roles. It is reported
that in response to TNF-␣ and IL-1␣, MEKK3 activation
results in the formation of an I␬B␣/NF-␬B/IKK complex,
which regulates rapid and transient NF-␬B activation, whereas
MEKK2 activation leads to the assembly of an I␬B␤/NF-␬B/
IKK complex, which mediates delayed and persistent NF-␬B
activation (210). Tpl2 appears to play important role in LPS
signaling, since Tpl2-deficient mice are resistant to endotoxemic lethality. However, those mice display relatively normal
NF-␬B activation as measured by nuclear translocation of
NF-␬B dimer in response to LPS (55). The role of Tpl2 in LPS
signaling is likely mediated through TNF-␣ signaling pathways. TNF-␣ activates the TNFRI/TRAF-2/RIP1 cascade,
leading to the activation of Tpl2, which phosphorylates p65 at
Ser276, resulting in NF-␬B-mediated gene transcription (55).
LPS activates multiple PKC isoforms, including PKC␣,
PKC␤, PKC␦ (40), PKC␨ (94), and PKC⑀ (35). Blocking
activation of those PKC isoforms using either isoform-specific
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kines [macrophage (or monocyte) colony-stimulating factor,
granulocyte-monocyte colony-stimulating factor, TNF-␣,
TNF-␤, IL-1␤, IL-2, IL-3, IL-5, IL-6, IL-12, IL-18], chemokines [IL-8; macrophage inflammatory protein (MIP)-1␣;
MIP-2; monocyte chemoattractant protein-1; cytokine-induced
neutrophil chemoattractant; growth-related oncogene (GRO)-␣,
GRO-␤, GRO-␥; regulated on activation, normal T cell expressed and secreted (RANTES)], adhesion molecules (ICAM-1,
VCAM-1, E-selection, P-selectin, MadCam-1), immunoreceptors, enzymes [iNOS, cyclooxygenase (COX)-2, phospholipase
A2, lipoxygenase (5-LO)], and acute-phase proteins (11, 26,
183). Animal studies have demonstrated that in vivo inhibition
of NF-␬B activation reduces LPS-induced mRNA and protein
expression of multiple proinflammatory cytokines and other
molecules that play critical roles in the pathophysiology of
sepsis (26, 144 –146).
Studies using mice deficient in those NF-␬B-dependent
genes have confirmed the important roles of those gene products in septic pathophysiology. TNF-␣ and IL-1␤ are two
primary mediators of the septic shock. Mice deficient in p55
TNF receptor (TNFRI) or p80 IL-1 receptor (IL-1RI) are
resistant to endotoxin lethality (2). Mice deficient in IL-1␤converting enzyme, the enzyme that catalyzes IL-1␤ production, are also resistant to LPS-induced endotoxic shock (138).
Adhesion molecules, ICAM-1, VCAM-1, and P-selectin, play
crucial role in neutrophil infiltration and activation, and endothelial injury, the pathological process that leads to septic
MOD/I. Deletion of ICAM-1 and VCAM-1 genes in mice
prevents endotoxemic myocardial dysfunction (199) and reduces LPS-induced lethality (255). The reduced mortality correlates with decreased neutrophil infiltration in the liver (255).
Targeted disruption of ICAM-1 and P-selectin genes improves
cardiac function and survival in mice overexpressing TNF-␣
(86). Polymicrobal sepsis induced by CLP causes a significant
increase in intestinal wall permeability in wild-type mice, and
this response is dramatically reduced in mice deficient in IL-6
(247). COX-2 and iNOS are the two major enzymes mediating
septic cardiovascular dysfunction and also contributing to septic MOD/I (see later discussion). Mice knockout of iNOS gene
reverses the depressed vasoconstrictor response, ameliorates
the impaired vasodilator response, prevents lung injury, and
improves survival rate in both LPS and CLP models of septic
shock (39, 98, 126). COX-2 knockout mice are also resistant to
LPS-induced inflammation and death (26). 5-LO is another
NF-␬B-regulated gene that contributes to septic MOD/I. Deletion of the 5-LO gene reduces LPS-induced tissue neutrophil
influx and injury in multiple organs (50).
Roles of NF-␬B in pathophysiology of septic shock. The
pathophysiological abnormalities of septic shock include cardiovascular dysfunction, intravascular coagulation, neutrophil
activation, and infiltration into multiple organs, increased microvascular endothelial barrier permeability, and MOD/I.
Blockade of NF-␬B pathway appears to correct all these
alterations in experimental animal models (Fig. 3). A major
feature of septic pathophysiology is cardiovascular dysfunction
manifested as refractory systemic hypotension, depressed cardiac contractility, vascular hyporeactivity to vasoconstrictors,
and impaired endothelium-dependent vasodilator response.
Compelling evidence indicates that excessive production of
NO and vasodilator prostaglandins are mainly responsible for
the septic cardiovascular dysfunction (26, 39, 98, 111, 122,
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Increased NF-␬B activity in sepsis and septic shock. Several
lines of evidence support the important role of NF-␬B activation in septic pathophysiology. As discussed above, NF-␬B is
activated by numerous bacteria, bacterial toxins, and proinflammatory mediators known to cause septic shock (Tables
1–3). NF-␬B activity induced by different bacterial pathogens
display different kinetics. NF-␬B activity as induced by ␤-glucans from pathogenic fungus, Pneumocystis carinii, is significantly slower in the induction of NF-␬B activity, and the
effect persists for a longer period compared with LPS (135).
LPS-induced NF-␬B activity is biphasic: an early phase occurred at 0.5–2 h, and a late phase occurred at 8 –12 h
poststimulation. LPS and other early-released inflammatory
mediators cause the early phase NF-␬B activation, and TNF
and IL-1␤ mediate the late-phase activation (92). The effect of
bacterial toxins on NF-␬B activity is dramatic and widespread,
leading to massive elevation in NF-␬B activity in all organs
studied (120, 145, 191, 195). This is consistent with the
involvement of multiple organs in septic shock.
NF-␬B activity is markedly increased in peripheral mononuclear cells from septic patients, and the level of NF-␬B
activity correlates with the severity of the disease as quantified
by Acute Physiology and Chronic Health Evaluation score (9).
NF-␬B activity is significantly higher in nonsurviving than that
in surviving patients (9, 22). A significant increased NF-␬B
activity is also observed in alveolar macrophages of patients
with septic lung injury (212).
Studies on animal models of septic shock induced either
by LPS (endotoxin model) or by cecal ligation and puncture
(CLP, polymicrobial model) have demonstrated that NF-␬B
inhibitors with divergent chemical properties and mechanisms of action protect animals from septic lethality (5, 106,
221). Molecules proven to protect mice from lethal endotoxemia (102) or to improve survival in severe sepsis patients (18)
exert their protective effect by inhibiting NF-␬B activation.
One such example is the anti-inflammatory cytokine IL-10. For
many years, IL-10 has been known to inhibit proinflammatory
cytokine production (87), improve bacteria-induced lung injury
(209), and induce survival in animals following endotoxemia
(102). It is now clear that IL-10 is a potent inhibitor of NF-␬B
activation (72). Human recombinant activated protein C improves survival in patients with severe sepsis and also inhibits
NF-␬B activation (26). Mice deficient in poly(ADP-ribose)
polymerase-1 have almost completely abrogated NF-␬B activity and are resistant to LPS-induced endotoxic shock (182).
Cells or animals developing endotoxin tolerance exhibit a
downregulated NF-␬B activity and reduced expression of NF␬B-dependent genes (159), when subsequently expose to endotoxin. This blunted NF-␬B response is believed to be the
result of increased I␬B␣ (217), p50, or p52 (23) expression or
because of a switch from p50/p65 heterodimer to p50/p50
homodimer formation (23). These results provide another piece
of evidence supporting a role of NF-␬B of in endotoxemia.
NF-␬B mediates the transcription of multiple proinflammatory genes. Transcriptional activation of multiple inflammatory
genes is the hallmark of septic pathophysiology. Studies using
promoter deletion mutagenesis and reporter gene analysis have
demonstrated that NF-␬B plays a crucial role in LPS- or
cytokine-activated promoter activity of over 200 genes, many
of which play important roles in the development of septic
shock (11, 26, 183). These genes include the following: cyto-
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188). NOS inhibitors reverse systemic hypotension in both
animal models of septic shock and septic patients (122, 188).
These inhibitors also restore vascular responsiveness to vasoconstrictors and ameliorate the depressed myocardial contractility associated with septic shock (122, 188). Compared with
wild-type mice, iNOS knockout mice show attenuated systemic hypotension and improved vascular contractility in both
LPS and CLP models of septic shock (39, 98). Blocking
prostaglandin production with the COX inhibitor ibuprofen
protects against hypotension and depression of cardiac function
associated with endotoxic shock and reduces endotoxic mortality (26, 111). Thus iNOS-generated NO and COX-2-produced vasodilator prostaglandins are mainly responsible for
septic cardiovascular dysfunction. NF-␬B plays a crucial role
in LPS-induced iNOS and COX-2 promoter activity as well as
iNOS and COX-2 gene expression (11, 183). Inhibition of
NF-␬B activation in vivo prevents LPS-induced iNOS and
COX-2 mRNA and protein expression (144 –146) and activities (146). Importantly, inhibition of NF-␬B activation corrects
cardiovascular functional abnormalities seen in septic shock.
Haudek and coworkers (93) demonstrated that cardiac specific
overexpression of I␬B␣ prevents LPS-induced repression of
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cardiac systolic and diastolic function. Inhibition of NF-␬B
pathway ameliorates the vascular derangement in both LPS and
polymicrobial models of septic shock (146, 221). Inhibition of
NF-␬B activation restores systemic hypotension (146, 221),
reverses the depressed vascular contractile response (219), and
restores the impaired endothelium-dependent vasodilator response (220, 228). Inhibition of IKK activity reduces cytokine
production and ameliorates systemic hypotension in a CLP
model of septic shock (268). Thus inhibition of NF-␬B activation is able to correct the cardiovascular functional abnormalities and helps to improve the outcome of endotoxic shock
in rodents.
Bacterial toxins and other inflammatory mediators released
during sepsis generate procoagulant signals. Sepsis, as it
progresses, almost invariably leads to hemostatic abnormalities
including disseminated intravascular coagulation (DIC). The
vast majority of patients with severe sepsis have increased
markers of coagulation, decreased anticoagulant proteins, and
reduced fibrinolytic activity (137). NF-␬B is involved in multiple steps of the coagulation cascade. NF-␬B mediates the
expression of tissue factor (TF) induced by LPS (179). Inhibition of NF-␬B activation by overexpressing I␬B␣ inhibits TF
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Fig. 3. NF-␬B activation plays a central role in the pathophysiology of septic shock. Bacteria and bacterial components activate NF-␬B through multiple
signaling pathways, leading to 1) expression of inflammatory cytokines such as TNF-␣, IFN-␥, IL-1␤, IL-6, IL-12, and IL-18, which cause fever and neurological
abnormalities and more importantly activate NF-␬B and its upstream signaling molecules, amplifying and perpetuating NF-␬B-mediated inflammatory response;
2) expression of tissue factor (TF), factor VIII, and plasminogen-activator inhibitor type-1 (PAI-1), leading to the activation of extrinsic and intrinsic coagulation
cascades and an impaired fibrinolysis, resulting in disseminated intravascular coagulation (DIC); 3) expression of inducible nitric oxide synthase (iNOS) and
cyclooxygenase-2 (COX-2), and excessive production of nitric oxide (NO) and vasodilator prostaglandins, resulting in systemic hypotension, repressed cardiac
contractility, and vascular hyporeactivity; 4) expression of adhesion molecules (ICAM-1, VCAM-1, E-selection, P-selectin) and chemokines [IL-8, macrophage
inflammatory protein (MIP)-1/2, monocyte chemoattractant protein (MCP)-1/2, cytokine-induced neutrophil chemoattractant (CINC)], leading to neutrophil
infiltration and activation, and the release of reactive oxygen species (ROS), reactive nitrogen species (RNS), and proteolytic enzymes, which cause microvascular
endothelial injury, increased endothelial barrier permeability and resultant multiple organ injury; and 5) expression of COX-2, 5-lipoxygenase (5-LO),
5-LO-activating protein (FLAP), leading to the production of proinjurious prostaglandins (PGs), leukotrienes (LTs), and thromboxane A2 (TBXA2) that cause
tissue injury. Those cascades of events are interrelated. Activation of coagulation promotes inflammatory mediator production and amplifies the process of
inflammation. Systemic hypotension and coagulation cause tissue hypoperfusion and hypoxia, setting up the precondition for the development of organ injury.
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bronchoalveolar lavage fluid from acute lung injury patients is
capable of activating NF-␬B in cultured epithelial cells (177),
and plasma from patients with postsurgical organ dysfunction
stimulates NF-␬B activity in healthy neutrophils, an effect that
is suppressed by NF-␬B inhibitors (75).
The impact of NF-␬B activation on the development of
septic MOD/I is both profound and extensive. NF-␬B activation is an integral part of the pathological response that leads to
the development of organ dysfunction/injury. In the rat brain,
LPS and IL-1␤ cause LTP in dentate gyrus, which is attenuated
by the NF-␬B inhibitor SN-50 (120). Inhibition of NF-␬B
activation with NF-␬B decoy ODN attenuates neuronal damage (240). In the heart, cardiac-specific overexpression of I␬B␣
protects against cardiac injury during trauma (33), and inhibition of NF-␬B activation prevents LPS-induced increase in
microvascular permeability (145). In the liver, inhibition of
NF-␬B activity suppresses LPS-induced inflammatory cytokine and adhesion molecule expression, reduces neutrophil
influx, and prevents LPS-induced increase in microvascular
endothelial permeability (144, 145). Intracellular delivery of
the NF-␬B decoy ODN in vivo suppresses endotoxin-induced
inflammatory cytokine production and fatal liver failure in
mice (180). NF-␬B activation also plays important role in
septic lung injury (72, 145). NF-␬B activity is significantly
elevated in patients with septic lung injury (212). Inhibition of
NF-␬B activation suppresses LPS-induced cytokine and adhesion molecule expressions, reduces lung neutrophil influx, and
prevents LPS-induced increase in lung microvascular endothelial barrier permeability in experimental animals (145). In the
kidney, NF-␬B is activated by LPS (191). Gene transfer of
truncated I␬B␣ prevents the tubulointerstitial injury (236).
Increased NF-␬B activity is detected in various regions of
gastrointestinal tract during endotoxemia (195). NF-␬B activation mediates TNF-␣-induced increase in intestinal epithelial
tight junction permeability (149). Anti-inflammatory cytokine
TGF-1␤ prevents gut inflammation by inhibiting NF-␬B activation. Failure of this TGF-1␤ negative regulatory mechanism
leads to a sustained NF-␬B activation and gut inflammation (1,
168). As discussed above, NF-␬B activation contributes to the
development of muscle wasting, which is another feature of
septic shock (29).
Effects of NF-␬B inhibition on the outcome of septic shock.
Studies using an LPS model of septic shock have consistently
demonstrated that blocking the NF-␬B pathway improves the
outcome of septic shock. Inhibition of NF-␬B activation using
inhibitors with diverse chemical properties and mechanisms of
action or using antisense ODN to p65 significantly increased
the survival rate of septic animals (Table 4). Some of the
reported results are impressive, improving survival rate from
0 –20% (LPS alone) to 80 –100% (LPS plus NF-␬B inhibitors).
However, studies using bacterial models of septic shock have
given conflicting results (Table 4). Studies using a CLP model
showed that inhibition of NF-␬B significantly improved survival rate in three studies but significantly reduced the survival
rate in one study (Table 4). Blockade of NF-␬B activation
using p65 antisense ODN had no effect on the survival rate of
septic mice induced by intravenous injection of S. aureus (85).
Mice deficient in the p50 subunit of NF-␬B showed a reduced
survival time compared with wild-type mice when challenged
by intraperitoneal injection of S. pneumoniae (216). There are
likely important differences between LPS and bacterial models
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gene and protein expressions in vital organs in vivo (22).
NF-␬B also mediates TNF-␣-induced factor VIII promoter
activity and gene expression (183). TF and factor VIII are the
two key factors initiating the extrinsic and intrinsic coagulation
pathways, leading to the activation of coagulation. Coagulation
can cause the release of inflammatory mediators such as
thrombin, which activates NF-␬B and induces NF-␬B-dependent gene expression (200), forming a positive feedback loop
to amplify the coagulation. NF-␬B mediates cytokine-induced
expression of plasminogen activator inhibitor type 1 (PAI-1)
(100). Increased PAI-1 level leads to impaired fibrinolysis,
further promoting coagulation. NF-␬B activation also mediates
cytokine-induced downregulation of thrombomodulin (TM)
expression (229). TM regulates coagulation by decreasing the
procoagulant activities of thrombin and by converting protein
C to activated protein C, which inactivates procoagulant factors FVa and FVIIIa. Impairment of TM-mediated anticoagulation mechanism further exacerbates coagulation, leading to
the development of DIC. DIC is one of the key factors
contributing to microvascular dysfunction and multiple organ
injury in sepsis (163). Activation of coagulation also promotes
the release of inflammatory mediators, which further amplify
the inflammatory response (163). Inhibition of NF-␬B activation prevents coagulation, resulting in improved outcome of
septic shock (22).
MOD/I is a devastating complication of sepsis and is the
major cause of death in these patients. As discussed above,
NF-␬B activation triggers a cascades of events that lead to
systemic hypotension and intravascular coagulation, which
cause tissue hypoperfusion and hypoxia, setting up the conditions for the development of MOD/I. NF-␬B mediates the
expression of multiple proinjurious and proinflammatory cytokines, chemokines, adhesion molecules, and enzymes and
enzyme cofactors (11, 183, 215). Proinjurious cytokines cause
or promote organ inflammation and injury directly and increase
endothelial barrier permeability (218). Proinflammatory enzymes, COX-2, 5-LO, and 5-LO-activating protein (FLAP)
synthesize and release proinjurious eicosanoids, and iNOS
synthesizes NO, leading to the subsequent formation of RNS,
all of which cause endothelial injury and contribute to the
pathophysiology of septic MOD/I (26, 74, 140). Adhesion
molecules and chemokines mediate neutrophil infiltration, adhesion, and activation at sites of inflammation (1, 32, 196),
which lead to the release of ROS, RNS, and proteolytic
enzymes, resulting in microvascular endothelial injury, increased endothelial barrier permeability, and ultimately
MOD/I. Thus NF-␬B activation is involved in multiple steps in
the cascades of molecular events that lead to the development
of MOD/I. Studies on animal models have demonstrated that
inhibition of NF-␬B activation diminishes gene and protein
expressions of those proinflammatory mediators, reduces tissue
neutrophil infiltration, and prevents LPS- or cytokine-induced
injury in multiple organs (1, 144, 145). Inhibition of IKK
activity has also been shown to reduce cytokine production and
to decrease neutrophil infiltration in lungs, colon, and liver and
to improve survival rate in a polymicrobial model of sepsis
(268). The clinical relevance of these animal studies is supported by studies showing that alveolar macrophages from
septic acute respiratory distress syndrome patients (212) and
neutrophils from patients with postoperative organ dysfunction
(75) have significantly increased NF-␬B activity. Moreover,
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Table 4. Effects of inhibiting NF-␬B activation on survival of septic animals
Survival Rate, %
Inhibitors
Septic
Treated
Days Followed
Ref. No.
LPS
60 mg/kg ip
60 mg/kg ip
20 mg/kg iv
GaIN ⫹ LPS
20 mg/kg ip
40 mg/kg ip
CLP
CLP
CLP
CLP
CLP
CLP
S. aureus iv
S. pneumoniae in
parthenolide
isohelenin
IRFI 042
PDTC
YS 51
cSN-50
parthenolide
15d-PGJ2
ciglitazone
glucan phosphate
scleroglucan
PDTC
p65 ODN
morphine
6
0
0
14
20
0
80
50
50
20
20
78
35
80
50
20
80
100
95
90
100
82
65
65
75
20
35
14
2
2
3
3
2
2
3
4
4
4
4
2
5
7
218
219
5
131
118
265
220
268
268
250
250
115
84
246
CLP, cecal ligation and puncture; PDTC, pyrrolidene dithiocarbamate; ODN, oligodeoxynucleotide; GaIN ⫹ LPS, D-galactosamine (20 mg ip) followed by
LPS (5 mg ip); IRFI 042, 5-emisuccinoyl-2-[2-(acetylthio)ethyl]-2,3-dihydro-4,6,7-trimethylbenzofuran; YS 51, 1-(beta-naphthylmethyl)-6,7-dihydroxy-1,2,3,4tetrahydroisoquinoline; 15d-PGJ2, 15-deoxy-delta(12,14)-prostaglandin J2.
in that bacterial challenge involves the effects not only of
bacterial toxins but also of bacterial infection, including the
activation of a robust host-defense response. In the LPS model,
blockade of NF-␬B pathway typically inhibited or terminated
the inflammatory and injury-promoting responses and, therefore, improved survival. In the bacterial model, however,
blocking NF-␬B activation inhibited both the inflammatory
and injury-promoting responses as well as the salutary hostdefense responses. The beneficial effects of inhibiting inflammatory response can be compromised by the impairment of
bacterial clearance capacity as a result of NF-␬B inhibition.
Thus the consequences of blocking NF-␬B action in the bacterial model of septic shock may depend on the balance of the
two opposite effects of NF-␬B inhibition. It has been demonstrated that treatment of mice with morphine markedly inhibited NF-␬B activation and proinflammatory gene expression,
reduced tissue neutrophil infiltration but increased bacterial
burden in lungs, spleen, and blood with a resultant increase in
mortality (246), consistent with this concept.
SUMMARY AND CONCLUDING REMARKS
NF-␬B is a group of pleiotropic transcription factors activated by numerous stimuli (⬎460 and still counting). Studies
in the past 10 years have uncovered multiple new pathways and
new mechanisms regulating NF-␬B activity. In addition to the
canonical pathways, NF-␬B activity is regulated by multiple
noncanonical pathways that lead to NF-␬B activation without
involving IKK activation, I␬B serine phosphorylation, and
proteasomal degradation. NF-␬B transcriptional activity is determined not only by the nuclear translocation of NF-␬B
dimers but also by other processes, including posttranslational
modification of NF-␬B protein, regulation of NF-␬B dimer
recruitment to target promoters, modification of histones surrounding NF-␬B binding sites, engagement or disengagement
of transcriptional cofactors and modulators, and interaction
with positive and negative regulators.
NF-␬B controls or contributes to the transcription of ⬎200
genes that are involved in a variety of physiological and
pathophysiological processes, particularly in immunity and
AJP-Lung Cell Mol Physiol • VOL
inflammation. NF-␬B is a critical regulator of cell differentiation, proliferation, and apoptosis and plays pivotal roles in
normal organ development and tumorigenesis. Aberrant regulation of NF-␬B activity has been implicated in the pathogenesis of multiple diseases, including autoimmune diseases, immune deficiencies and disorders, inflammatory diseases, I/R
injury, cancers, and neurodegenerative disorders.
NF-␬B activation is a central molecular event leading to the
development of septic shock (Fig. 3). NF-␬B is activated by a
variety of bacteria and bacterial components and is the final
target of all these septic shock-inducing agents. Studies using
animal models of septic shock have shown that NF-␬B activity
is markedly elevated in multiple organs. NF-␬B activity is also
markedly increased in patients with septic shock, and the
degree of NF-␬B activity correlates with the severity of the
disease. Greater NF-␬B activity is associated with higher rates
of mortality and worse clinical outcome. NF-␬B activation
mediates the transcriptional expression of large number proinflammatory genes that play important roles in pathophysiology
of sepsis. Mice deficient in those NF-␬B-dependent genes are
resistant to the development of septic shock and sepsis-related
death in both endotoxin and CLP models. Importantly, blockade of NF-␬B pathway corrects the pathological abnormalities
seen in septic shock in animal models. Inhibition of NF-␬B
activation reduces multiple inflammatory gene expression, restores systemic hypotension, prevents myocardial dysfunction,
diminishes intravascular coagulation, and decreases tissue neutrophil influx and microvascular endothelial barrier permeability. Inhibition of NF-␬B activation is also coupled to the
prevention of multiple organ injury and improves the survival
in rodent models of septic shock.
The critical role of NF-␬B activation in septic pathophysiology and the effectiveness of inhibiting NF-␬B activation in
correcting septic abnormalities indicate that targeting NF-␬B is
a desired therapeutic strategy for the treatment of septic shock.
This idea is supported fully by the significantly improved
survival rate in the LPS model of septic shock. However, in
response to bacterial challenge, the bacterial burden remains a
major issue, because inhibition of NF-␬B activation also im290 • APRIL 2006 •
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Model
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NF-␬B IN SEPTIC PATHOPHYSIOLOGY
14.
15.
16.
17.
18.
19.
20.
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pairs the bacterial clearance capability. Unfortunately, the
innate immune response controls both bacterial clearance and
the inflammatory response that causes the pathophysiology of
septic shock, and in this sense the two are interwoven. Therefore, at this time it would be unrealistic to inhibit one response
without affecting the other. One potentially useful strategy
would be to inhibit NF-␬B activation in a cell-specific manner
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initiating step of sepsis-induced MOD/I. If inhibition of NF-␬B
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NF-␬B activation. Another possible approach may be a selective modulation of NF-␬B activity. This strategy requires an
initial assessment of the immune state and bacterial load; thus,
in the absence of clear bacterial burden, inhibition of NF-␬B
may be beneficial in mitigating the inflammatory response,
whereas a significant bacterial burden would lead to a detrimental outcome following inhibition of NF-␬B. It is possible
that with the development of targeted cell-specific strategies
inhibiting NF-␬B activation, the consequences of sepsis inducing lung injury and multiorgan failure can be prevented.
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