Translation Control: A Multifaceted
Regulator of Inflammatory Response
Barsanjit Mazumder, Xiaoxia Li and Sailen Barik
This information is current as
of April 13, 2017.
Subscription
Permissions
Email Alerts
This article cites 98 articles, 45 of which you can access for free at:
http://www.jimmunol.org/content/184/7/3311.full#ref-list-1
Information about subscribing to The Journal of Immunology is online at:
http://jimmunol.org/subscription
Submit copyright permission requests at:
http://www.aai.org/About/Publications/JI/copyright.html
Receive free email-alerts when new articles cite this article. Sign up at:
http://jimmunol.org/alerts
The Journal of Immunology is published twice each month by
The American Association of Immunologists, Inc.,
1451 Rockville Pike, Suite 650, Rockville, MD 20852
Copyright © 2010 by The American Association of
Immunologists, Inc. All rights reserved.
Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
References
J Immunol 2010; 184:3311-3319; ;
doi: 10.4049/jimmunol.0903778
http://www.jimmunol.org/content/184/7/3311
Translation Control: A Multifaceted Regulator of
Inflammatory Response
Barsanjit Mazumder,* Xiaoxia Li,† and Sailen Barik‡
R
egulating gene expression at the level of protein translation offers several benefits, including rapidity of response and reversibility. Translational control can be
subdivided into two major classes: global and transcript specific.
Although the first mechanism regulates most transcripts, the second permits translation regulation of a limited ensemble of proteins. Transcript-specific regulation is generally mediated by the
interaction of RNA-binding proteins with cognate cis-elements in
the untranslated region (UTR) of the target transcripts, causing
translational repression (1, 2). Although not significantly emphasized, an important role of translational control in regulating
acute inflammation is evident from emerging studies. It is obligatory for the cells of the immune system to rapidly activate the
inflammatory protein synthesis in response to infection or its
*Department of Biology, Geology and Environmental Science, Center for Gene Regulation in Health and Disease, College of Science, Cleveland State University, Cleveland,
OH 44115; †Department of Immunology, Cleveland Clinic Foundation Lerner Research Institute, Cleveland, OH 44195; and ‡Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688
Received for publication December 14, 2009. Accepted for publication January 26, 2010.
This work was supported by National Institutes of Health Grant RO1HL79164 and
American Heart Association Grant-in-Aid 0855555D (to B.M.), RO1AI060632 (to X.
L.), and RO1AI059267 (to S.B.).
Address correspondence and reprint requests to Dr. Barsanjit Mazumder or Dr. Sailen
Barik, Department of Biology, Geology and Environmental Science, Center for Gene
Regulation in Health and Disease, College of Science, Cleveland State University, 2121
Euclid Avenue, Cleveland, OH 44115 (B.M.) or Department of Biochemistry and
Molecular Biology, College of Medicine, University of South Alabama, 307 University
Boulevard, Mobile, AL 36688-0002 (S.B.). E-mail addresses: [email protected]
or [email protected]
www.jimmunol.org/cgi/doi/10.4049/jimmunol.0903778
blockage when they are no longer needed. Translational control
offers a strategic advantage to these cells, because the use of the preexisting mRNAs bypass the lengthy nuclear control mechanisms
(e.g., transcription, splicing, and transport). At the same time, it
provides the reversibility through modifications of the regulatory
intermediates, mainly via reversible phosphorylation. Together,
these two features allow rapid activation or termination of synthesis of a specific protein or group of proteins required for inflammation.
Acute inflammation is a highly orchestrated, tissue-based
response to trauma incited by tissue injury or microbial invasion of the host (3, 4). Initiated by responsive leukocytes and
lymphocytes, a key component of the process is the trafficking
of inflammatory cells to the sites of injury or infection. The
cytokine/receptor interactions on the surface of these cells
culminate in the expression of new gene products that efficiently kill or injure the invading organisms. However, uncontrolled production of inflammatory products is injurious
to host cells and even leads to neoplastic transformation (5).
Therefore, endogenous mechanisms have evolved to limit the
production of inflammatory molecules and permit the resolution of the inflammatory response (3, 6). In-depth studies of
these mechanisms are important because defects in the pathway may contribute to the progression of chronic inflammatory disorders, and the pathway itself may present
targets for novel anti-inflammatory therapeutic strategies.
Outstanding past reviews summarized the resolution of inflammation (3, 6), as well as stress-mediated, global translational
control mechanisms (2, 7–9). A recent article reviewed how
a number of cytokine mRNAs can be regulated at the level of
mRNA stability (10). In addition, the role of one particular
RNA-binding complex in the control of inflammation was the
subject of a recent review (11). In this article, our goal is to present
and defend the hypothesis that transcript-specific translational
Abbreviations used in this paper: 4E-BP, 4E-binding protein; ARE, AU-rich element;
COX-2, cyclooxygenase-2; Cp, ceruloplasmin; DAPK, death-associated protein kinase;
eIF, eukaryotic translation initiation factor; DICE, differentiation induced control element; EPRS, glutamyl-prolyl-tRNA synthetase; GAIT, IFN-g–activated inhibitor of
translation; HIF, hypoxia-inducible factor; hnRNP, heterogeneous nuclear ribonucleoprotein; IRES, internal ribosome entry site; IRF, IFN regulatory factor; miRNA, microRNA; MMP, matrix metalloproteinase; MRE, microRNA response element; mTOR,
mammalian target of rapamycin; PKR, protein kinase R; RFLAT, RANTES factor of
late-activated T lymphocytes; SOCS, suppressor of cytokine signaling; TIA, T cell intracellular Ag; TIAR, T cell intracellular Ag-1–related protein; UTR, untranslated region; VEGF, vascular endothelial growth factor; ZIPK, zipper-interacting protein kinase.
Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
A robust innate immune response is essential to the protectionofallvertebratesfrominfection,butitoftencomeswith
the price tag of acute inflammation. If unchecked, a runaway inflammatory response can cause significant tissue
damage, resulting in myriad disorders, such as dermatitis,
toxicshock,cardiovasculardisease,acutepelvicandarthritic
inflammatory diseases, and various infections. To prevent
such pathologies, cells have evolved mechanisms to rapidly
and specifically shut off these beneficial inflammatory activities before they become detrimental. Our review of recent literature, including our own work, reveals that the
most dominant and common mechanism is translational
silencing,inwhichspecificregulatoryproteinsorcomplexes
are recruited to cis-acting RNA structures in the untranslated regions of single or multiple mRNAs that code for the
inflammatory protein(s). Enhancement of the silencing
function may constitute a novel pharmacological approach
to prevent immunity-related inflammation. The Journal
of Immunology, 2010, 184: 3311–3319.
3312
BRIEF REVIEWS: TRANSLATIONAL REGULATION OF INFLAMMATION
control is the prime determinant of the onset, progression, and
resolution of acute inflammation.
Translational regulations offer stringent control of highly inflammatory
cytokines
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
TNF-a, which is synthesized and secreted by lymphocytes, mast
cells, and activated macrophages, has multiple proinflammatory
functions geared toward protection of the host from infection.
TNF-a induces fever via induction of PGE2 synthesis by the
hypothalamic vascular endothelium (12), activates synthesis of
complement factors (3), and recruits leukocytes to the sites of
infection via induction of adhesion molecules (13, 14). The high
potency and diversity of proinflammatory functions require
stringent control of TNF-a expression. Indeed, expression of
TNF-a in unstimulated mouse peritoneal macrophages is extremely low, in part because of low mRNA expression and as
a result of a block in translation (15). Treatment of macrophages
with LPS, a cell wall component of Gram-negative bacteria, induces a 10,000-fold increase in TNF-a protein secretion resulting from simultaneous activation of transcription and
derepression of the translational blockade (16).
Ourknowledge ofthetranslationalcontrolmechanismshasbeen
advanced by the discovery of several proteins that bind AU-rich
elements (AREs). Found in the 39 UTRs of various mRNAs, AREs
are of enormous physiological significance because they recruit
protein factors that regulate the stability of the target mRNA.
Interestingly, a number of ARE-containing mRNAs, which include TNF-a and cyclooxygenase-2 (COX-2), are associated with
the inflammatory response. The embedded ARE sequence clearly
offers protection against the overexpression of TNF-a, because
transgenic mice that express TNF-a mRNA lacking ARE exhibit
elevated levels of circulating TNF-a and developed joint- and gutassociated immunopathology (17). Although TNF-a is an arm of
innate immunity, its highly inflammatory property must have
necessitated multiple checkpoints for stringent control.
The ARE-based mechanisms are orchestrated by a complex ensemble of RNA-binding proteins that are recruited to ARE, such as
heterogeneous nuclear ribonucleoprotein (hnRNP)-A1, HuR,
T cell intracellular Ag (TIA)-1, TIA-1–related protein (TIAR),
and TTP. Basal translation of TNF-a mRNA can be silenced by
hnRNP-A1 binding to the ARE element. Phosphorylation of
hnRNP-A1 by Mnk, a kinase downstream of p38 MAPK, decreases its affinity for the ARE and, thus, reactivates TNF-a
translation (18). Two other ARE-binding proteins, TIA-1 and
TIAR, constitutively bind to TNF-a mRNA in unstimulated and
stimulated macrophages (19, 20). TIA-1 has multiple roles in the
regulation of TNF-a expression that can be negative or positive,
depending on context. More TNF-a mRNA associates with
polysomes in peritoneal macrophages isolated from TIA-1–null
mice compared with control mice, demonstrating its function in
transcript-specific translational silencing (19). The inhibitory
mechanism has yet to be determined, but it may involve sequestration in cytoplasmic mRNA storage depots, known as stress
granules, which contain TIA-1 and TIAR (21).
Translational silencing by TIA-1/TIAR is not limited to TNF-a
mRNA. COX-2, which catalyzes the rate-limiting step of PG
synthesis during inflammation, is also silenced by TIA-1 binding to
an ARE in the 39 UTR (22). Like TNF-a, the powerful, multifactorial inflammatory protein COX-2 is under translational
control by multiple pathways. In epithelial cells, COX-2 translation is silenced by yet another protein CUG-binding protein 2
(23) that is predominantly nuclear but rapidly translocates to the
cytoplasm following stress. Interestingly, CUG-binding protein 2
binds to two sets of AREs within the COX-2 39 UTR, and unlike
the previous mechanism, it stabilizes COX-2 mRNA, although it
inhibits its translation nonetheless. Another critical target of TIAR
is human matrix metalloproteinase (MMP)-13, which is expressed
in chronic inflammation and cancer and may remodel the extracellular matrix (24). MMP-13 mRNA is translationally silenced by
an alternately spliced form of TIAR (25). Genome-wide analysis of
TIA-1–bound transcripts identified a bipartite stem-loop as the
target element and predicted that up to 3000 transcripts may
contain this element (26). An important physiological role of the
TIA-1/TIAR translational silencing pathway is suggested by the
uncontrolled cartilage inflammation and arthritis in TIA-1–null
mice (19) and in transgenic mice that overexpress ARE-less TNF-a
(17). Studies with TIA-1–deficient macrophages also showed that
HuR-mediated translational silencing requires TIA-1. Furthermore, myeloid-restricted overexpression of HuR inhibits the
macrophage inflammatory response in vivo (27). In summary,
translational control by TIA-1/TIAR and others is critical for the
maintenance of the basal, noninflammatory state in several cell
types. Reciprocally, its derepression is necessary for maximal induction of target transcripts during the early initiation phase of
acute inflammation.
The first line of innate antiviral defense in host cells is a robust
production of type I IFNs (-a and -b) (28) induced by the
transcription factor IFN regulatory factor (IRF)7, which, in turn,
is regulated by the translational repressors 4E-binding protein
(4E-BP)1 and 4E-BP2 (29). Mouse embryonic fibroblasts lacking these repressors are resistant to multiple viruses, such as influenza, encephalomyocarditis, vesicular stomatitis, and Sindbis.
This enhanced antiviral response is caused exclusively by the
significant upregulation of IRF7 translation (29). Contrary to its
positive role in innate and adaptive immunity, the activation of
mammalian target of rapamycin (mTOR) in phagocytic cells can
also limit the inflammatory response. mTOR downregulates the
expression of proinflammatory cytokines IL-12 and -23; reciprocally, the inhibition of mTOR by rapamycin promotes the
expression of IL-6, -12, and -23 and TNF-a and downregulates
the expression of the anti-inflammatory cytokine IL-10 (30).
Despite the multifaceted role of mTOR in immunity (31), it
remains unknown whether its activation directly influences the
de novo translation of the mRNAs coding for these cytokines,
perhaps via a common RNA element. The lack of knowledge is
probably due to the preferential attention bestowed on the upstream and downstream signaling cascade of mTOR, rather than
identifying the target mRNAs. It is also possible that mTOR
targets a critical transcription factor common to this array of
cytokine genes. The recent report of mTOR-mediated direct
translational repression of IRF7 mRNA is consistent with this
notion (29).
Studies of IL-10 have provided strong evidence for the role of
translational control in anti- and proinflammatory pathways (Fig.
1). mRNAs of inflammatory proteins (e.g., TNF-a, COX-2, and
MMP-2) are translationally repressed by ARE-binding proteins
in the 39 UTRs. Inflammatory stimuli activate p38 MAPK,
which targets ARE-binding proteins and derepresses the translation. As an anti-inflammatory protein, IL-10 blocks this process
by inhibiting p38 MAPK (32) (Fig. 1). Interestingly, occupancy
of the adenosine receptor by its ligands activates translation of
IL-10 mRNA, thus playing an important role in the anti-
The Journal of Immunology
3313
inflammatory activity of these ligands (33). However, in
a proinflammatory role, IL-10 stimulates ferritin translation by
reducing the affinity of the translational repressor, the iron response element-binding protein, to the 59 UTR of ferritin
mRNA (34). Considering the role of ferritin in iron sequestration, this may lead to hyperferritinemia and limited iron
availability for the progenitor cells in bone marrow, a condition
typically seen in the anemia of chronic inflammation (Fig.1).
Activation of T lymphocytes
The proliferation and migration of T lymphocytes promote
inflammation and the eukaryotic translation initiation factor
(eIF)4E-BP kinase mTOR plays a pivotal role in this process.
mTOR targets Kruppel-like factor 2, an essential transcription
factor of CCR7 and L-selectin that is crucial for the migration of
CD8+ T lymphocytes into lymph nodes (35). Indeed, G1 to S
phase progression in IL-2–stimulated T lymphocytes can be
blocked by rapamycin, an inhibitor of mTOR (36). In apparent
contrast, a recent report revealed that inhibition of mTOR has
immunostimulatory effects. This report showed that rapamycin
significantly enhances the quantity and quality of virus-specific
CD8+ T cells and identified eIF4E as a downstream effector
molecule of mTOR (37). In addition, a recent study showed that
activation of mTOR is required for regulatory and effector T cell
lineage commitment (38). A subsequent study also showed that
single IgG IL-1–related receptor, a negative regulator of IL-1R
and TLR signaling, controls Th17 cell development and effector
function by blocking the IL-1–induced activation of mTOR
(39). Together, these results show that translational control by
mTOR is critical for the regulation of adaptive immunity and
raise new hope for the management of inflammation by its
pharmacological manipulations.
Chemoattraction of T lymphocytes
The chemoattraction of T lymphocytes to the site of injury is an
obligatory component of inflammation, and RANTES is a major
player in this process (40). A rheostat function of regulating
RANTES expression at the site of inflammation is crucial for the
rapid response to stress, cytokines, and other proinflammatory
factors in the local microenvironment of T lymphocytes (41).
This precise control is achieved by regulating the translation of
RANTES factor of late-activated T lymphocytes (RFLAT)-1
(Fig. 2). RFLAT-1 is a transcription factor that activates the
RANTES gene; although its mRNA remains constant in resting
and activated T cells, the protein is expressed only 3–5 d after
T cell activation (42). This occurs through an interesting
mechanism, in which two upstream open-reading frames and
a highly structured 59 UTR of RFLAT-1 mRNA promote
translational silencing. Conversely, phosphorylation of 4E-BP
FIGURE 2. Chemoattraction of T lymphocytes by RANTES is under
translation control. RFLAT, a transcription factor of RANTES, is silenced at
the level of translation in unstimulated cells by 4E-BP. Phosphorylation of 4EBP by mTOR promotes dissociation of 4E-BP, allowing assembly of the
translation initiation factors (eIFs) on RFLAT mRNAs. This activates the
translation of RFLAT protein and promotes the transcription of RANTES
gene. Expression of RANTES (blue circles) is required for the chemoattraction
of T lymphocytes to the sites of injury.
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
FIGURE 1. Pro- and anti-inflammatory axis of IL-10 depends on translation regulation. Left, Inflammatory stimuli activate p38 MAPK that disengages ARE
binding proteins and derepresses the translation of inflammatory proteins. In a global anti-inflammatory role, IL-10 negatively regulates this process by abrogating
the activation by p38 MAPK. Right, Occupancy of the adenosine receptors by its ligands relieves the imposed translational repression of IL-10 mRNA and
activates the synthesis of IL-10 protein (blue circles). As a proinflammatory molecule, IL-10 stimulates ferritin translation by removing the translational repressor
(the iron response element-binding protein) from 59 UTR. Overproduction of ferritin causes sequestration of available iron (rust-colored circles) for bone
marrow, leading to the characteristic anemia of inflammation.
3314
BRIEF REVIEWS: TRANSLATIONAL REGULATION OF INFLAMMATION
and eIF4E itself by mTOR and p38 MAPK/ERK rescues
RFLAT-1 mRNA from silencing (Fig. 2) (41). The extracellular
signals that activate these kinases are unknown. Nevertheless, the
translational control of RFLAT clearly helps to precisely control
RANTES, which, in turn, may be required to constantly monitor
the environment as T lymphocytes move through extracellular
spaces to the sites of injury (41).
Neutrophil influx
NK cell-mediated cytotoxicity
Contact-dependent cytotoxicity is critical for innate immunity
and depends upon the rapid synthesis of perforin and granzymes (50). There is compelling evidence that blockage of
perforins and granzyme mRNA translation underlies the
minimal cytotoxicity of resting NK cells and that removal of
this blockage is crucial for NK cell activation (51). The
finding that the activation signal(s) cause an immediate release
of the translation brake of the killer proteases could offer
a novel opportunity for therapeutic intervention.
Monocyte adhesion and platelet activation
Adhesion of monocytes and activation of platelets are vital steps in
hemostasis and inflammation (52). A series of observations made
by Zimmerman and colleagues showed that both processes pass
through checkpoints executed by translational control of some
key molecules. Engagement of P-selectin gp1 to the plasma
membrane of monocytes delivers outside-in signals that activate
mTOR and, hence, phosphorylate 4E-BP. The latter then activates translation of urokinase plasminogen activator receptor,
a critical cell surface protease receptor required for cell adhesion
and cell surface phenotype (53). Thrombin stimulation induces
platelet adhesion and aggregation, and the activated platelets cause
translational activation of Bcl-3 (54), the oncogene product of B
cell lymphoma-3. The secretion of Bcl-3 mediates adhesion and
outside-in signaling of these cells by engagement of aIIb/b3 integrin. The lack of transcriptional activity in the platelets, a longstanding observation, argues that Bcl-3 may be regulated at the
level of translation. Metabolic labeling of thrombin-activated
platelet showed that Bcl-3 is indeed activated directly at the level of
translation and requires activation of mTOR and 4E-BP phosphorylation (54).
Macrophage survival in injured tissue
FIGURE 3. A translationally regulated enzyme 15-lipoxygenase controls
neutrophil influx. A neutrophil (magenta) is recruited to the tissue from the
lumen. This process is mediated by leukotriene B4 synthesized from arachidonate and catalyzed by 5-lipoxygenase within the neutrophil. The recruitment
of neutrophil in the tissue is depicted to bring in arachidonate that produces
lipoxin using translationally regulated enzyme, 15-lipoxygenase. Note that this
enzyme is different from the 5-lipoxygenase within the neutrophil. The regulation requires recruitment of the hRNPK complex (green) to DICE, a novel
RNA element in the 39 UTR of 15-lipoxygenase mRNA that can block 60S
ribosomal subunit joining and inhibit translation. Tissue lipoxin (blue circles),
generated by 15-lipoxygenase, exits and blocks further neutrophil influx. DICE,
differentiation induced control element.
Low levels of oxygen and glucose, as well as high concentrations of
lactate and reductive metabolites, characterize the surroundings of
the injured tissues (55). To maintain viability and activity in such
challenging conditions, the cells of the innate immune system must
adopt a strategy to maintain the cellular ATP pool. The longstanding question of how the cells achieve this feat has been answered by studies from Johnson and colleagues (56). Using gene
knockout mice, these studies showed the essential role of hypoxiainducible factor (HIF)-1a in the process of myeloid cell survival
and inflammation. The expression of the mRNAs of the glycolytic
enzymes phosphoglycerate kinase (57), lactate dehydrogenase
(57), pyruvate kinase M (58), and glucose transporter-1 (59) is
HIF-1a–dependent and required for survival of the macrophages.
In agreement with this hypothesis, genetic abrogation of HIF-1a
causes profound defects in myeloid cell aggregation, motility, invasiveness, and bacterial killing (56). The 59 UTR of HIF-1a
mRNA is highly structured and contains an internal ribosome
entry site (IRES) responsible for translational activation (60, 61).
The IRES-mediated translation of HIF-1a under hypoxic conditions is particularly important, because hypoxia inhibits capdependent translation by reducing the availability of eIF4E and by
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
Neutrophilsaremajorplayersininnateimmunityandprovideearly
links between the innate and adaptive inflammatory responses.
Upon activation by cognate signals, the neutrophils rapidly
translate their constitutive mRNAs. For example, translation of
IL-6 soluble receptor is induced when neutrophils are activated by
platelet-activating factor (43), a signaling phosphopeptide implicated in homeostatic and injurious inflammation (44). The
mechanisms that limit neutrophil influx demonstrate nicely how
the signal to resolve inflammation has been embedded in the signal
for initiation. Neutrophil-derived arachidonate serves as substrate
for neutrophil 5-lipoxygenase to generate the inflammatory leukotriene B4. However, the infiltrating neutrophils also deliver
arachidonate to tissue cells that express 15-lipoxygenase; this catalyzes the conversion of arachidonate to lipoxins, which inhibit
neutrophil influx (3, 45) (Fig. 3). Consistent with these findings,
a defect in lipoxin-mediated anti-inflammatory activity was reported in the cystic fibrosis airway (46). 15-Lipoxygenase that
produces lipoxins, a signal for inflammation resolution, can be
regulated at the level of translation by the binding of hnRNP-K
and E1 to the differentiation induced control element in its 39
UTR (47), which blocks the 60S ribosomal subunit from joining
(Fig. 3) (48). Unexpectedly, the activation of c-Src kinase causes
phosphorylation of hnRNP-K, abrogating its RNA-binding
activity and derepressing 15-lipoxygenase mRNA translation
(Fig. 3) (49). These results add to the mounting evidence for the
importance of translational control in the interface between
pro- and anti-inflammatory responses, in this case from neutrophils using arachidonate in a context-specific fashion.
The Journal of Immunology
3315
teresting twist, IL-1b also activates NF-kB (69), and NF-kB activates the transcription of miR-146a (70) and IL-8 genes (71).
Clearly, this is an intricate feedback inhibition operating at
multiple levels, such that the initial trigger, IL-1b, rapidly activates the two chemokines via NF-kB and, at the same time, induces the synthesis of a silencer miRNA of the chemokines. Such
controls limit the severe inflammation that would otherwise accompany the innate immune response of the pulmonary epithelia.
Controlling the immune and inflammatory responses by microRNAs
Translational control of the negative regulators of inflammation
A major breakthrough in translational regulation is the recent
recognition of the RNA interference pathway, variations of which
are found in all metazoan cells. In the RNA interference pathway,
small noncoding RNA molecules, broadly called microRNAs
(miRNAs), bind to partially complementary sequences in the 39
UTR of target mRNAs, called miRNA response element (MRE),
and repress translation (64). In the dendritic cells, bacterial LPS
or viral dsRNA binds to TLRs, triggering a signaling cascade that
ultimately leads to T cell activation and elaboration of a plethora
of inflammatory cytokines, including the type I IFNs. Recent
studies showed how miRNAs could impose restraints on this
process to protect the cells from uncontrolled immune response.
Microarray analysis of macrophages after exposure to dsRNA (or
IFN-b) revealed that miR-155 is the only miRNA that was
substantially upregulated by LPS and dsRNA, suggesting that
miR-155 is a common target of a broad range of inflammatory
mediators (65). In-depth studies revealed that miR-155 silenced
transcripts that code for several proinflammatory proteins, such as
the Fas-associated death domain protein, I-k B kinase-«, TNFR
superfamily-interacting serine-threonine kinase 1, and TAK-1–
associated binding protein-2. An unexpected observation was that
miR-155 also targeted the TNF-a mRNA 39 UTR and actually
enhanced TNF-a translation, the mechanism of which remained
unexplored (66). In fact, transgenic mice expressing recombinant
miR-155 produced higher levels of TNF-a when exposed to LPS
and were hypersensitive to LPS-induced septic shock, suggesting
that the TNF-a–stimulating role of miR-155 may have a dominant effect in pathology (66). Altogether, these results show
a balancing act of miR-155 in acute inflammation and sepsis,
perhaps in a context-dependent manner.
In another study (67), miR-9 was found to be upregulated in
polymorphonuclear neutrophils and monocytes by multiple proinflammatory signals, such as TLR4, TLR2, and TLR7/8 agonists, and by the proinflammatory molecules LPS, TNF-a, and
IL-1b but not by IFN-g. A number of these agonists activate the
proinflammatory transcription factor NF-kB that, in turn, acts as
a transcription factor to induce miR-9 expression. Interestingly,
NF-kB translation was reciprocally silenced by miR-9 via an
MRE in the 39 UTR of the NF-kB mRNA. Overall, these data
suggest that NF-kB rapidly increases the expression of miR-9
that operates a feedback control of the NF-kB–dependent acute
inflammatory response triggered by multiple signals.
Evidence of miRNA-mediated silencing of inflammatory genes
in nonimmunecellshas only begunto appear,and a recent example
comes from studies of pulmonary inflammation. The epithelial
lining of the mammalian lungs is constantly exposed to inflammatory signals in the inhaled air. A recent study revealed that
stimulation with IL-1b, a proinflammatory cytokine, results in
a rapid increase in miR-146a expression in pulmonary cells (68).
The increased miRNA-146a promoted translational silencing of
the proinflammatory chemokines IL-8 and RANTES. In an in-
Response to ILs and IFNs are negatively regulated by the
members of a family of Src homology 2 domain-containing
adaptor molecules, suppressor of cytokine signaling (SOCS). Expression of SOCS-1 is repressed at the level of translation initiation
by two upstream open reading frames in the 59 UTR (72). Induction of RNA helicase activity relieves the repression, permitting
an increase in SOCS-1 protein expression and subsequent inhibition of the cytokine-induced response. Regulation of SOCS-1
exemplifies how translational control of a single gene can be crucial
for simultaneous control of an array of inflammatory genes.
The proinflammatory cytokine IL-6 is negatively regulated by
anunsuspectedplayer,thetumorsuppressorp53,adefectinwhich
leads to the pathogenesis of rheumatoid arthritis (73, 74) and
autoimmune inflammation (75). In both diseases, lack of p53
function leads to overexpression of IL-6 (74) and a heightened
response to LPS and IFN (75). Interestingly, p53 mRNA itself is
a target of the translational silencing mechanism that requires
a region of its 39 UTR (76). This region is also targeted by the
RNA-binding protein HuR that relieves the translational repression (77, 78). Together, these findings show that translation
upregulation of p53 can be important in resolving inflammation.
Translational control of IFN-g expression
The entire IFN-g axis, including the synthesis of IFN-g and its
downstream signaling, is under translational control, as we describe
in this section and the next. Production of IFN-g by T lymphocytes
is subject to at least two distinct translational control mechanisms.
IL-18 (originally designated as IFN-g–inducing factor) is an epithelial and stromal cell product and is a potent and specific inducer
of IFN-g transcription in T lymphocytes. In a rat glomerular nephritis model, IL-18 mRNA is translationally silenced by its 59
UTR, resulting in minimal induction of IFN-g (Fig. 4) (79).
Additionally, T cell expression of IFN-g is autoregulated at the
level of translation, again by a 59 UTR element, but using an unusual and indirect mechanism. A pseudoknot in the IFN-g 59
UTR recruits and activates dsRNA-activated protein kinase R
(PKR) (Fig. 4) (80), which, in turn, phosphorylates eIF2a and
inhibits IFN-g translation. Unexpectedly, global protein synthesis
remains unaltered, suggesting that the cellular region of PKR activation remains highly restricted. Therefore, in this feedback
mechanism, the pseudoknot essentially acts as a PKR sensor, preventing the overproduction of IFN-g.
IFN-g–activated inhibitor of translation pathway: the translational
master regulator of IFN-g–induced inflammation
IFN-g is a major cytokine activator of macrophages that contributes to innate immunity toward pathogens (81). A series of
studies from our group and other investigators discovered
a unique translational silencing mechanism that is triggered by
IFN-g exposure of monocytic cells (Fig. 4) (82–89). We found
robust transcriptional activation of ceruloplasmin (Cp) within
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
phosphorylation of translation initiation factor eIF2a (62, 63),
thus creating a highly compromised condition. Under these conditions, IRES-mediated translation might be an effective means to
sustain the synthesis of the survival proteins for the macrophages. It
is tempting to speculate that resolution of inflammation results
from inhibition of IRES activity, downregulation of HIF-1a, and
the subsequent loss of monocytes/macrophages from the site of
injury.
3316
BRIEF REVIEWS: TRANSLATIONAL REGULATION OF INFLAMMATION
2 h of IFN-g treatment, but this was followed by translation silencing 16–24 h later. Cp is an inflammatory, acute-phase protein made by liver, monocytes, and macrophages, and it has
a documented role in monocyte-mediated lipoprotein oxidation,
bactericidal activity, and iron homeostasis (90). Translational
silencing of Cp requires the binding of a protein complex (IFNg–activated inhibitor of translation [GAIT] complex) to a specific element (GAIT element) in the 39 UTR of Cp mRNA (82,
85). The GAIT element is a degenerate 29-nucleotide bipartite
hairpin with features that distinguish it from other translational
control elements. Using genetic and biochemical approaches,
four protein constituents of the GAIT complex have been
identified: ribosomal protein L13a, glutamyl-prolyl-tRNA synthetase (EPRS), NS1-associated protein-1, and GAPDH (Fig. 4)
(84, 86). Interestingly, two of the proteins are released from preexisting cytosolic macromolecular complexes that are critical
components of the protein synthesis pathway: EPRS is released
from the aminoacyl-tRNA multisynthetase complex (86), and
L13a is released from the large ribosomal subunit (84). In both
cases, release is initiated by IFN-g and requires phosphorylation
of the released protein (84, 91). Assembly of the GAIT complex
occurs in two stages (Fig. 4). During the first stage, which
is complete within ∼4 h, phosphorylated EPRS binds to NS1associated protein-1 to form a nonfunctional, pre-GAIT
complex. Approximately 12 h later, ribosome-free, phosphorylated L13a joins GAPDH and the pre-GAIT complex to form
the functional quaternary GAIT complex that binds the GAIT
element and blocks translation. Surprisingly, despite the phosphorylation and release of L13a and EPRS from their parent
complexes, global protein synthesis remains unaltered. As part
of the GAIT complex, phospho-L13a binds the translation
GAIT pathway regulates an inflammation-responsive
posttranscriptional operon
Posttranscriptional operons in eukaryotes represent a powerful
mechanism for regulating functionally related genes simultaneously
on the same cue. This mechanism uses specific RNA-binding
proteins that recognize structural elements common to the mRNAs
of that family (95, 96). With this concept in mind, and knowing the
inflammatory property of Cp, we recently hypothesized that the
GAIT pathway may regulate a whole cohort of mRNAs belonging
to an inflammation-related posttranscriptional operon. This hypothesis is also based on the high abundance of GAIT complex
components and stoichiometric release of L13a and EPRS from
their parental complexes (84, 86). To test this, we conducted
a genome-wide screen for target mRNAs of GAIT-mediated
translational silencing in IFN-g–activated monocytes (89) through
an analysis of polysome-bound and -unbound mRNA pools. This
led us to identify a cohort of mRNAs that follow the same pattern
of regulation as Cp. Functional mapping of the GAIT-like elements in the 39 UTRs of these putative targets validated the
translational silencing mechanism. Importantly, many of these
mRNAs coded for inflammatory proteins, such as chemokines and
their receptors and proteins important in cytokine response and
signaling. The chemokines and their receptors, for example, are
responsible for activation-directed migration of leukocytes to the
sites of inflammation during immune surveillance (97), which is
now also recognized as a major contributor to the pathogenesis of
inflammatory disease, such as atherosclerosis (98, 99), and neoplastic, infectious, allergic, and autoimmune diseases (100). A
potential therapeutic approach would be to enhance the formation
of the GAIT complex, perhaps by triggering the phosphorylation
and release of L13a from its 60S ribosomal depot. This approach
could be used to identify a powerful anti-inflammatory drug because of its ability to silence all inflammatory mRNAs of this
posttranscriptional operon using a natural mechanism.
Conclusion and Future Directions
Translational regulation, primarily through the recruitment of
specific proteins to cognate sequences in the UTRs of the target
mRNAs, is gaining new recognition. By virtue of its mechanism,
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
FIGURE 4. Control of the IFN-g axis and the GAIT paradigm of translational silencing. IL-18, an epithelial cell-derived factor, induces IFN-g in
T cells. The synthesis of both IL-18 and IFN-g is under translational control
by sequence elements at the 59 UTR of their cognate mRNAs (left). In myeloid cells (such as macrophages), IFN-g induces the initial inflammatory
signal that is eventually silenced by an ordered assembly of the GAIT complex
(subunits in yellow). Formation of GAIT complex requires the release of its
subunit proteins from their parental complex triggered by phosphorylation
events (phosphate groups in red). The binding of silencing-competent GAIT
complex at the GAIT elements of the 39 UTRs of the mRNAs (the members
of the posttranscriptional operon) encoding inflammatory proteins directly
blocks translation by intercepting the recruitment of 40S ribosomal subunit.
Translational silencing of a group of inflammatory proteins by the GAIT
pathway resolves inflammation.
initiation factor eIF4G of the cap-binding eIF4F complex,
thereby preventing the formation of the 48S preinitiation
complex (88). Recent studies identified Ser77 of L13a as the
single site for IFN-g–inducible phosphorylation (92) and
death-associated protein kinase (DAPK) and zipper-interacting
protein kinase (ZIPK) as the responsible kinases (92). Interestingly, DAPK-ZIPK itself is also a target of GAIT-mediated translational silencing. Thus, the GAIT mechanism
provides a self-limiting pathway that relies on the DAPK-ZIPKL13a negative feedback module.
A clinically significant GAIT-containing gene, the translation
of which is also silenced by the GAIT complex described above, is
vascular endothelial growth factor (VEGF) (93). The sustained
expression of VEGF is obligatory for the hypoxic response. In
a recent report, hypoxia was shown to override GAIT-mediated
repression of VEGF translation observed in normoxia (93, 94)
through the formation of alternate RNA secondary structure in
the GAIT region. The ability of the hypoxia to override the
translational repression could help the decision-making process
of macrophages simultaneously exposed to opposing inflammatory and hypoxic signals.
The Journal of Immunology
Acknowledgments
We offer our sincere apology to many scientists whose work could not be included in the references because of space limitations. We are extremely thankful
to Dr. Joseph D. Fontes, University of Kansas School of Medicine, for critical
reading and proofreading of the late-stage manuscript.
Disclosures
The authors have no financial conflicts of interest.
References
1. Mazumder, B., V. Seshadri, and P. L. Fox. 2003. Translational control by the 39UTR: the ends specify the means. Trends Biochem. Sci. 28: 91–98.
2. Sonenberg, N., and A. G. Hinnebusch. 2009. Regulation of translation initiation
in eukaryotes: mechanisms and biological targets. Cell 136: 731–745.
3. Nathan, C. 2002. Points of control in inflammation. Nature 420: 846–852.
4. Kumar, V., A. K. Abbas, and N. Fausto. 2004. Robbins and Cotran’s Pathologic Basis of
Disease, 7th Ed. Saunders, Philadelphia.
5. Mantovani, A., P. Allavena, A. Sica, and F. Balkwill. 2008. Cancer-related inflammation.
Nature 454: 436–444.
6. Gilroy, D. W., T. Lawrence, M. Perretti, and A. G. Rossi. 2004. Inflammatory
resolution: new opportunities for drug discovery. Nat. Rev. Drug Discov. 3: 401–416.
7. Dever, T. E. 2002. Gene-specific regulation by general translation factors. Cell
108: 545–556.
8. Holcik, M., and N. Sonenberg. 2005. Translational control in stress and apoptosis.
Nat. Rev. Mol. Cell Biol. 6: 318–327.
9. Sonenberg, N., and A. G. Hinnebusch. 2007. New modes of translational control
in development, behavior, and disease. Mol. Cell 28: 721–729.
10. Anderson, P. 2008. Post-transcriptional control of cytokine production. Nat.
Immunol. 9: 353–359.
11. Mukhopadhyay, R., J. Jia, A. Arif, P. S. Ray, and P. L. Fox. 2009. The GAIT system:
a gatekeeper of inflammatory gene expression. Trends Biochem. Sci. 34: 324–331.
12. Warren, J. S. 1990. Interleukins and tumor necrosis factor in inflammation. Crit.
Rev. Clin. Lab. Sci. 28: 37–59.
13. Tsang, C. M., C. K. Wong, W. K. Ip, and C. W. Lam. 2005. Synergistic effect of
SCF and TNF-a on the up-regulation of cell-surface expression of ICAM-1 on
human leukemic mast cell line (HMC)-1 cells. J. Leukoc. Biol. 78: 239–247.
14. Edelstein, L. C., A. Pan, and T. Collins. 2005. Chromatin modification and the
endothelial-specific activation of the E-selectin gene. J. Biol. Chem. 280: 11192–
11202.
15. Beutler, B., N. Krochin, I. W. Milsark, C. Luedke, and A. Cerami. 1986. Control
of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance.
Science 232: 977–980.
16. Han, J., T. Brown, and B. Beutler. 1990. Endotoxin-responsive sequences control
cachectin/tumor necrosis factor biosynthesis at the translational level. J. Exp. Med.
171: 465–475.
17. Kontoyiannis, D., M. Pasparakis, T. T. Pizarro, F. Cominelli, and G. Kollias. 1999.
Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10:
387–398.
18. Buxadé, M., J. L. Parra, S. Rousseau, N. Shpiro, R. Marquez, N. Morrice, J. Bain,
E. Espel, and C. G. Proud. 2005. The Mnks are novel components in the control
of TNF a biosynthesis and phosphorylate and regulate hnRNP A1. Immunity 23:
177–189.
19. Piecyk, M., S. Wax, A. R. Beck, N. Kedersha, M. Gupta, B. Maritim, S. Chen, C. Gueydan,
V. Kruys, M. Streuli, and P. Anderson. 2000. TIA-1 is a translational silencer that selectively
regulates the expression of TNF-a. EMBO J. 19: 4154–4163.
20. Gueydan, C., L. Droogmans, P. Chalon, G. Huez, D. Caput, and V. Kruys. 1999.
Identification of TIAR as a protein binding to the translational regulatory AU-rich
element of tumor necrosis factor a mRNA. J. Biol. Chem. 274: 2322–2326.
21. Kedersha, N. L., M. Gupta, W. Li, I. Miller, and P. Anderson. 1999. RNA-binding
proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of
mammalian stress granules. J. Cell Biol. 147: 1431–1442.
22. Dixon, D. A., G. C. Balch, N. Kedersha, P. Anderson, G. A. Zimmerman,
R. D. Beauchamp, and S. M. Prescott. 2003. Regulation of cyclooxygenase-2
expression by the translational silencer TIA-1. J. Exp. Med. 198: 475–481.
23. Mukhopadhyay, D., C. W. Houchen, S. Kennedy, B. K. Dieckgraefe, and S. Anant.
2003. Coupled mRNA stabilization and translational silencing of cyclooxygenase-2
by a novel RNA binding protein, CUGBP2. Mol. Cell 11: 113–126.
24. Oh, J., R. Takahashi, S. Kondo, A. Mizoguchi, E. Adachi, R. M. Sasahara, S. Nishimura,
Y. Imamura, H. Kitayama, D. B. Alexander, et al. 2001. The membrane-anchored
MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis. Cell 107: 789–800.
25. Yu, Q., S. J. Cok, C. Zeng, and A. R. Morrison. 2003. Translational repression of
human matrix metalloproteinases-13 by an alternatively spliced form of T-cellrestricted intracellular antigen-related protein (TIAR). J. Biol. Chem. 278: 1579–1584.
26. López de Silanes, I., S. Galbán, J. L. Martindale, X. Yang, K. Mazan-Mamczarz,
F. E. Indig, G. Falco, M. Zhan, and M. Gorospe. 2005. Identification and
functional outcome of mRNAs associated with RNA-binding protein TIA-1. Mol.
Cell. Biol. 25: 9520–9531.
27. Katsanou, V., O. Papadaki, S. Milatos, P. J. Blackshear, P. Anderson, G. Kollias,
and D. L. Kontoyiannis. 2005. HuR as a negative posttranscriptional modulator in
inflammation. Mol. Cell 19: 777–789.
28. Garcı́a-Sastre, A., and C. A. Biron. 2006. Type 1 interferons and the virus-host
relationship: a lesson in détente. Science 312: 879–882.
29. Colina, R., M. Costa-Mattioli, R. J. Dowling, M. Jaramillo, L. H. Tai, C. J. Breitbach,
Y. Martineau, O. Larsson, L. Rong, Y. V. Svitkin, et al. 2008. Translational control of
the innate immune response through IRF-7. Nature 452: 323–328.
30. Weichhart, T., G. Costantino, M. Poglitsch, M. Rosner, M. Zeyda, K. M. Stuhlmeier,
T. Kolbe, T. M. Stulnig, W. H. Hörl, M. Hengstschläger, et al. 2008. The TSCmTOR signaling pathway regulates the innate inflammatory response. Immunity 29:
565–577.
31. Weichhart, T., and M. D. Säemann. 2009. The multiple facets of mTOR in
immunity. Trends Immunol. 30: 218–226.
32. Kontoyiannis, D., A. Kotlyarov, E. Carballo, L. Alexopoulou, P. J. Blackshear,
M. Gaestel, R. Davis, R. Flavell, and G. Kollias. 2001. Interleukin-10 targets p38
MAPK to modulate ARE-dependent TNF mRNA translation and limit intestinal
pathology. EMBO J. 20: 3760–3770.
33. Németh, Z. H., C. S. Lutz, B. Csóka, E. A. Deitch, S. J. Leibovich, W. C. Gause,
M. Tone, P. Pacher, E. S. Vizi, and G. Haskó. 2005. Adenosine augments IL-10
production by macrophages through an A2B receptor-mediated posttranscriptional
mechanism. J. Immunol. 175: 8260–8270.
34. Tilg, H., H. Ulmer, A. Kaser, and G. Weiss. 2002. Role of IL-10 for induction of
anemia during inflammation. J. Immunol. 169: 2204–2209.
35. Sinclair, L. V., D. Finlay, C. Feijoo, G. H. Cornish, A. Gray, A. Ager, K. Okkenhaug,
T. J. Hagenbeek, H. Spits, and D. A. Cantrell. 2008. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat.
Immunol. 9: 513–521.
36. Morice, W. G., G. J. Brunn, G. Wiederrecht, J. J. Siekierka, and R. T. Abraham.
1993. Rapamycin-induced inhibition of p34cdc2 kinase activation is associated
with G1/S-phase growth arrest in T lymphocytes. J. Biol. Chem. 268: 3734–3738.
37. Araki, K., A. P. Turner, V. O. Shaffer, S. Gangappa, S. A. Keller, M. F. Bachmann,
C. P. Larsen, and R. Ahmed. 2009. mTOR regulates memory CD8 T-cell differentiation. Nature 460: 108–112.
38. Delgoffe, G. M., T. P. Kole, Y. Zheng, P. E. Zarek, K. L. Matthews, B. Xiao,
P. F. Worley, S. C. Kozma, and J. D. Powell. 2009. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:
832–844.
39. Gulen, M. F., Z. Kang, K. Bulek, W. Youzhong, T. W. Kim, Y. Chen, C. Z. Altuntas,
K. Bak-Jenson, M. J. McGeachy, J. S. Do, et al. 2010. The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway
and mTOR Kinase Activation. Immunity .
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
this form of regulation is fast and capable of being mRNA and
pathway specific (7, 9, 10). The silencing is rapid because the
molecular components involved in the process are constitutively
present in the cytoplasm or form rapidly once the commitment to
silencing is made. In general, the feedback silencing force slowly
builds up while the immune response is functioning and then is
rapidly deployed when the time is right. It seems that the onset of
the silencing is programmed into the initiation of immune response itself. In the prototype GAIT-mediated silencing, the
DAPK-ZIPK kinase cascade that phosphorylates L13a exhibits
a rapid induction of kinase activities between 12 and 16 h of IFNg treatment, despite essentially unchanged kinase levels (92).
This delay imposes a deliberate restriction to form the silencingcompetent GAIT complex and allows the expression of the IFNg–induced inflammatory proteins at early hours. Clearly, these
mechanisms offer new targets of pharmacological interventions
against the overproduction of many inflammatory proteins by
promoting the modifications of the regulatory intermediates.
An interesting new area of study will be to understand whether
and how two silencing elements on the same proinflammatory
mRNA interact. This may include two homologous elements (i.e.,
belonging to the same family), such as two GAIT sequences, or
heterologous ones (of different families), such as a GAIT and an
MRE. The cis-acting location of both in the same 39 UTR may
allow novel forms of interaction between their cognate complexes.
We envision that such interactions may also affect specific genes of
the inflammatory pathways, allowing control by multiple physiological signals. Insights gained from the translational-silencing
mechanisms targeting single or multiple mRNAs should ultimately lead to novel anti-inflammatory approaches exploiting the
endogenous cellular pathways of inflammation resolution.
3317
3318
BRIEF REVIEWS: TRANSLATIONAL REGULATION OF INFLAMMATION
67. Bazzoni, F., M. Rossato, M. Fabbri, D. Gaudiosi, M. Mirolo, L. Mori, N. Tamassia,
A. Mantovani, M. A. Cassatella, and M. Locati. 2009. Induction and regulatory
function of miR-9 in human monocytes and neutrophils exposed to proinflammatory
signals. Proc. Natl. Acad. Sci. USA 106: 5282–5287.
68. Perry, M. M., S. A. Moschos, A. E. Williams, N. J. Shepherd, H. M. Larner-Svensson,
and M. A. Lindsay. 2008. Rapid changes in microRNA-146a expression negatively
regulate the IL-1beta-induced inflammatory response in human lung alveolar epithelial
cells. J. Immunol. 180: 5689–5698.
69. Yoshida, Y., A. Kumar, Y. Koyama, H. Peng, A. Arman, J. A. Boch, and P. E. Auron.
2004. Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique
TRAF6- and p65-dependent mechanism. J. Biol. Chem. 279: 1768–1776.
70. Taganov, K. D., M. P. Boldin, K. J. Chang, and D. Baltimore. 2006. NF-kappaBdependent induction of microRNA miR-146, an inhibitor targeted to signaling
proteins of innate immune responses. Proc. Natl. Acad. Sci. USA 103: 12481–
12486.
71. Ahn, K. S., and B. B. Aggarwal. 2005. Transcription factor NF-kappaB: a sensor
for smoke and stress signals. Ann. N. Y. Acad. Sci. 1056: 218–233.
72. Gregorieff, A., S. Pyronnet, N. Sonenberg, and A. Veillette. 2000. Regulation of
SOCS-1 expression by translational repression. J. Biol. Chem. 275: 21596–21604.
73. Firestein, G. S., F. Echeverri, M. Yeo, N. J. Zvaifler, and D. R. Green. 1997. Somatic
mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proc.
Natl. Acad. Sci. USA 94: 10895–10900.
74. Yamanishi, Y., D. L. Boyle, S. Rosengren, D. R. Green, N. J. Zvaifler, and
G. S. Firestein. 2002. Regional analysis of p53 mutations in rheumatoid arthritis
synovium. Proc. Natl. Acad. Sci. USA 99: 10025–10030.
75. Zheng, S. J., S. E. Lamhamedi-Cherradi, P. Wang, L. Xu, and Y. H. Chen. 2005.
Tumor suppressor p53 inhibits autoimmune inflammation and macrophage
function. Diabetes 54: 1423–1428.
76. Fu, L., and S. Benchimol. 1997. Participation of the human p53 3’UTR in translational repression and activation following gamma-irradiation. EMBO J. 16: 4117–
4125.
77. Mazan-Mamczarz, K., S. Galbán, I. López de Silanes, J. L. Martindale, U. Atasoy,
J. D. Keene, and M. Gorospe. 2003. RNA-binding protein HuR enhances p53
translation in response to ultraviolet light irradiation. Proc. Natl. Acad. Sci. USA
100: 8354–8359.
78. Galbán, S., J. L. Martindale, K. Mazan-Mamczarz, I. López de Silanes, J. Fan,
W. Wang, J. Decker, and M. Gorospe. 2003. Influence of the RNA-binding
protein HuR in pVHL-regulated p53 expression in renal carcinoma cells. Mol.
Cell. Biol. 23: 7083–7095.
79. Garcia, G. E., Y. Xia, G. Ku, R. J. Johnson, C. B. Wilson, and L. Feng. 2003. IL18 translational inhibition restricts IFN-g expression in crescentic glomerulonephritis. Kidney Int. 64: 160–169.
80. Ben-Asouli, Y., Y. Banai, Y. Pel-Or, A. Shir, and R. Kaempfer. 2002. Human
interferon-g mRNA autoregulates its translation through a pseudoknot that activates the interferon-inducible protein kinase PKR. Cell 108: 221–232.
81. Schroder, K., P. J. Hertzog, T. Ravasi, and D. A. Hume. 2004. Interferon-g: an
overview of signals, mechanisms and functions. J. Leukoc. Biol. 75: 163–189.
82. Mazumder, B., and P. L. Fox. 1999. Delayed translational silencing of ceruloplasmin transcript in gamma interferon-activated U937 monocytic cells: role of the
39 untranslated region. Mol. Cell. Biol. 19: 6898–6905.
83. Mazumder, B., V. Seshadri, H. Imataka, N. Sonenberg, and P. L. Fox. 2001.
Translational silencing of ceruloplasmin requires the essential elements of mRNA
circularization: poly(A) tail, poly(A)-binding protein, and eukaryotic translation
initiation factor 4G. Mol. Cell. Biol. 21: 6440–6449.
84. Mazumder, B., P. Sampath, V. Seshadri, R. K. Maitra, P. E. DiCorleto, and
P. L. Fox. 2003. Regulated release of L13a from the 60S ribosomal subunit as
a mechanism of transcript-specific translational control. Cell 115: 187–198.
85. Sampath, P., B. Mazumder, V. Seshadri, and P. L. Fox. 2003. Transcript-selective
translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 39 untranslated region. Mol. Cell. Biol. 23:
1509–1519.
86. Sampath, P., B. Mazumder, V. Seshadri, C. A. Gerber, L. Chavatte, M. Kinter,
S. M. Ting, J. D. Dignam, S. Kim, D. M. Driscoll, and P. L. Fox. 2004. Noncanonical function of glutamyl-prolyl-tRNA synthetase: gene-specific silencing of
translation. Cell 119: 195–208.
87. Chaudhuri, S., K. Vyas, P. Kapasi, A. A. Komar, J. D. Dinman, S. Barik, and
B. Mazumder. 2007. Human ribosomal protein L13a is dispensable for canonical
ribosome function but indispensable for efficient rRNA methylation. RNA 13:
2224–2237.
88. Kapasi, P., S. Chaudhuri, K. Vyas, D. Baus, A. A. Komar, P. L. Fox, W. C. Merrick,
and B. Mazumder. 2007. L13a blocks 48S assembly: role of a general initiation factor
in mRNA-specific translational control. Mol. Cell 25: 113–126.
89. Vyas, K., S. Chaudhuri, D. W. Leaman, A. A. Komar, A. Musiyenko, S. Barik, and
B. Mazumder. 2009. Genome-wide polysome profiling reveals an inflammationresponsive posttranscriptional operon in gamma interferon-activated monocytes.
Mol. Cell. Biol. 29: 458–470.
90. Musci, G. 2001. Ceruloplasmin, the unique multi-copper oxidase of vertebrates.
Protein Pept. Lett. 8: 159–169.
91. Arif, A., J. Jia, R. Mukhopadhyay, B. Willard, M. Kinter, and P. L. Fox. 2009.
Two-site phosphorylation of EPRS coordinates multimodal regulation of noncanonical translational control activity. Mol. Cell 35: 164–180.
92. Mukhopadhyay, R., P. S. Ray, A. Arif, A. K. Brady, M. Kinter, and P. L. Fox.
2008. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating
inflammatory gene expression. Mol. Cell 32: 371–382.
93. Ray, P. S., and P. L. Fox. 2007. A post-transcriptional pathway represses monocyte
VEGF-A expression and angiogenic activity. EMBO J. 26: 3360–3372.
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017
40. Schall, T. J., K. Bacon, K. J. Toy, and D. V. Goeddel. 1990. Selective attraction of
monocytes and T lymphocytes of the memory phenotype by cytokine RANTES.
Nature 347: 669–671.
41. Nikolcheva, T., S. Pyronnet, S. Y. Chou, N. Sonenberg, A. Song, C. Clayberger,
and A. M. Krensky. 2002. A translational rheostat for RFLAT-1 regulates
RANTES expression in T lymphocytes. J. Clin. Invest. 110: 119–126.
42. Song, A., Y. F. Chen, K. Thamatrakoln, T. A. Storm, and A. M. Krensky. 1999.
RFLAT-1: a new zinc finger transcription factor that activates RANTES gene
expression in T lymphocytes. Immunity 10: 93–103.
43. Lindemann, S. W., C. C. Yost, M. M. Denis, T. M. McIntyre, A. S. Weyrich, and
G. A. Zimmerman. 2004. Neutrophils alter the inflammatory milieu by signaldependent translation of constitutive messenger RNAs. Proc. Natl. Acad. Sci. USA
101: 7076–7081.
44. Prescott, S. M., G. A. Zimmerman, D. M. Stafforini, and T. M. McIntyre. 2000.
Platelet-activating factor and related lipid mediators. Annu. Rev. Biochem. 69: 419–445.
45. Levy, B. D., C. B. Clish, B. Schmidt, K. Gronert, and C. N. Serhan. 2001. Lipid
mediator class switching during acute inflammation: signals in resolution. Nat.
Immunol. 2: 612–619.
46. Karp, C. L., L. M. Flick, K. W. Park, S. Softic, T. M. Greer, R. Keledjian,
R. Yang, J. Uddin, W. B. Guggino, S. F. Atabani, et al. 2004. Defective lipoxinmediated anti-inflammatory activity in the cystic fibrosis airway. Nat. Immunol. 5:
388–392.
47. Ostareck, D. H., A. Ostareck-Lederer, M. Wilm, B. J. Thiele, M. Mann, and
M. W. Hentze. 1997. mRNA silencing in erythroid differentiation: hnRNP K and
hnRNP E1 regulate 15-lipoxygenase translation from the 39 end. Cell 89: 597–606.
48. Ostareck, D. H., A. Ostareck-Lederer, I. N. Shatsky, and M. W. Hentze. 2001.
Lipoxygenase mRNA silencing in erythroid differentiation: The 3’UTR regulatory
complex controls 60S ribosomal subunit joining. Cell 104: 281–290.
49. Ostareck-Lederer, A., D. H. Ostareck, C. Cans, G. Neubauer, K. Bomsztyk,
G. Superti-Furga, and M. W. Hentze. 2002. c-Src-mediated phosphorylation of
hnRNP K drives translational activation of specifically silenced mRNAs. Mol. Cell.
Biol. 22: 4535–4543.
50. Yokoyama, W. M., S. Kim, and A. R. French. 2004. The dynamic life of natural
killer cells. Annu. Rev. Immunol. 22: 405–429.
51. Fehniger, T. A., S. F. Cai, X. Cao, A. J. Bredemeyer, R. M. Presti, A. R. French,
and T. J. Ley. 2007. Acquisition of murine NK cell cytotoxicity requires the
translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity
26: 798–811.
52. Weyrich, A. S., S. Lindemann, and G. A. Zimmerman. 2003. The evolving role of
platelets in inflammation. J. Thromb. Haemost. 1: 1897–1905.
53. Mahoney, T. S., A. S. Weyrich, D. A. Dixon, T. McIntyre, S. M. Prescott, and
G. A. Zimmerman. 2001. Cell adhesion regulates gene expression at translational
checkpoints in human myeloid leukocytes. Proc. Natl. Acad. Sci. USA 98: 10284–10289.
54. Weyrich, A. S., D. A. Dixon, R. Pabla, M. R. Elstad, T. M. McIntyre, S. M. Prescott,
and G. A. Zimmerman. 1998. Signal-dependent translation of a regulatory protein,
Bcl-3, in activated human platelets. Proc. Natl. Acad. Sci. USA 95: 5556–5561.
55. Saadi, S., L. E. Wrenshall, and J. L. Platt. 2002. Regional manifestations and
control of the immune system. FASEB J. 16: 849–856.
56. Cramer, T., Y. Yamanishi, B. E. Clausen, I. Förster, R. Pawlinski, N. Mackman,
V. H. Haase, R. Jaenisch, M. Corr, V. Nizet, et al. 2003. HIF-1a is essential for
myeloid cell-mediated inflammation. Cell 112: 645–657.
57. Firth, J. D., B. L. Ebert, C. W. Pugh, and P. J. Ratcliffe. 1994. Oxygen-regulated
control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A
genes: similarities with the erythropoietin 39 enhancer. Proc. Natl. Acad. Sci. USA
91: 6496–6500.
58. Semenza, G. L., P. H. Roth, H. M. Fang, and G. L. Wang. 1994. Transcriptional
regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1.
J. Biol. Chem. 269: 23757–23763.
59. Ebert, B. L., J. D. Firth, and P. J. Ratcliffe. 1995. Hypoxia and mitochondrial
inhibitors regulate expression of glucose transporter-1 via distinct Cis-acting sequences. J. Biol. Chem. 270: 29083–29089.
60. Lang, K. J., A. Kappel, and G. J. Goodall. 2002. Hypoxia-inducible factor-1a
mRNA contains an internal ribosome entry site that allows efficient translation
during normoxia and hypoxia. Mol. Biol. Cell 13: 1792–1801.
61. Zhou, J., M. Callapina, G. J. Goodall, and B. Brüne. 2004. Functional integrity of
nuclear factor kappaB, phosphatidylinositol 39-kinase, and mitogen-activated
protein kinase signaling allows tumor necrosis factor alpha-evoked Bcl-2 expression
to provoke internal ribosome entry site-dependent translation of hypoxia-inducible
factor 1alpha. Cancer Res. 64: 9041–9048.
62. Koumenis, C., C. Naczki, M. Koritzinsky, S. Rastani, A. Diehl, N. Sonenberg,
A. Koromilas, and B. G. Wouters. 2002. Regulation of protein synthesis by hypoxia via
activation of the endoplasmic reticulum kinase PERK and phosphorylation of the
translation initiation factor eIF2alpha. Mol. Cell. Biol. 22: 7405–7416.
63. Tinton, S. A., and P. M. Buc-Calderon. 1999. Hypoxia increases the association of
4E-binding protein 1 with the initiation factor 4E in isolated rat hepatocytes. FEBS
Lett. 446: 55–59.
64. Hannon, G. J., and J. J. Rossi. 2004. Unlocking the potential of the human genome with RNA interference. Nature 431: 371–378.
65. O’Connell, R. M., K. D. Taganov, M. P. Boldin, G. Cheng, and D. Baltimore.
2007. MicroRNA-155 is induced during the macrophage inflammatory response.
Proc. Natl. Acad. Sci. USA 104: 1604–1609.
66. Tili, E., J. J. Michaille, A. Cimino, S. Costinean, C. D. Dumitru, B. Adair,
M. Fabbri, H. Alder, C. G. Liu, G. A. Calin, and C. M. Croce. 2007. Modulation
of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock.
J. Immunol. 179: 5082–5089.
The Journal of Immunology
94. Ray, P. S., J. Jia, P. Yao, M. Majumder, M. Hatzoglou, and P. L. Fox. 2009. A
stress-responsive RNA switch regulates VEGFA expression. Nature 457: 915–919.
95. Keene, J. D. 2007. RNA regulons: coordination of post-transcriptional events.
Nat. Rev. Genet. 8: 533–543.
96. Keene, J. D., and S. A. Tenenbaum. 2002. Eukaryotic mRNPs may represent
posttranscriptional operons. Mol. Cell 9: 1161–1167.
3319
97. Weber, C., and R. R. Koenen. 2006. Fine-tuning leukocyte responses: towards
a chemokine ‘interactome’. Trends Immunol. 27: 268–273.
98. Lambert, M. P., B. S. Sachais, and M. A. Kowalska. 2007. Chemokines and thrombogenicity. Thromb. Haemost. 97: 722–729.
99. Libby, P. 2002. Inflammation in atherosclerosis. Nature 420: 868–874.
100. Gerard, C., and B. J. Rollins. 2001. Chemokines and disease. Nat. Immunol. 2:
108–115.
Downloaded from http://www.jimmunol.org/ by guest on April 13, 2017