Revie

ws

and

featu

reart

icle

s

Current reviews of allergy and clinical immunology(Supported by an unrestricted educational grant from Novartis Pharmaceuticals Corporation)

Series editor: Harold S. Nelson, MD

Signal transducer and activator of transcriptionsignals in allergic disease

Weiguo Chen, PhD, and Gurjit K. Khurana Hershey, MD, PhD Cincinnati, Ohio

This activity is available for CME credit. See page 42A for important information.

Signal transducer and activator of transcription (STAT)

proteins are a group of transcription factors that transmit

signals from the extracellular milieu of cells to the nucleus.

They are crucial for the signaling of many cytokines that are

mediators of allergic inflammation and impact various cell

types critical to allergy including epithelial cells, mast cells,

lymphocytes, dendritic cells, and eosinophils. Dysregulation of

STAT signaling has been implicated in allergic disease,

highlighting the importance of these ubiquitous molecules in

allergic inflammation and the potential of these pathways as a

target for therapeutic intervention. This review will summarize

the current understanding of the roles of STAT signaling in

allergic disease and the potential of targeting STATs for the

treatment of allergic disorders, emphasizing recent

observations. (J Allergy Clin Immunol 2007;119:529-41.)

Key words: Allergy, STAT, cytokine, JAK-STAT, review

During allergic inflammation, preformed and newlysynthesized cytokines are released that contribute to thepathology seen in allergic diseases. These cytokines havea wide range of activities on different cell types. Theyexert their effects by binding to specific cell surfacereceptors and inducing the expression of relevant targetgenes. The discovery of signal transducer and activator oftranscription (STAT) proteins over 15 years ago provideda key molecular link between the binding of a cytokine toits cell surface receptor and the induction of specific genes.This link between the interferon (IFN) receptor and genetranscription in the first report of a STAT protein resulted

From the Division of Allergy and Immunology, Cincinnati Children’s Hospital

Medical Center, and the Department of Pediatrics, University of Cincinnati.

Disclosure of potential conflict of interest: The authors have declared that they

have no conflict of interest.

Received for publication December 14, 2006; revised January 3, 2007;

accepted for publication January 5, 2007.

Reprint requests: Gurjit K. Khurana Hershey, MD, PhD, Division of Allergy and

Immunology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet

Avenue, MLC 7028, Cincinnati, OH 45229. E-mail: Gurjit.Hershey@

cchmc.org.

0091-6749/$32.00

� 2007 American Academy of Allergy, Asthma & Immunologydoi:10.1016/j.jaci.2007.01.004

in the discovery of the Janus kinase (JAK)-STAT path-way.1 Many interleukins and members of the hematopoi-etin family utilize this pathway to transduce their signals.These distinct factors transmit their signals via 4 JAK and7 STAT molecules. JAKs constitutively associated withthe receptors via conserved box-1 motifs are broughtinto proximity following ligand-receptor interactionsleading to transphosphorylation and resultant activationof JAKs. Activated JAKs then phosphorylate specific ty-rosine residues in the cytoplasmic region of the receptorthat can serve as docking sites for STAT monomers.STAT monomers associate with the phosphorylated tyro-sine sites and become tyrosine phosphorylated through theaction of JAKs. Activated STATs are released from the re-ceptor, dimerize, translocate to the nucleus, bind specificcanonical DNA elements, and initiate cytokine-specificgene transcription. The preferred binding sites for STATtranscription factors consist of the palindromic motifTTC(Xn)GAA, where the number of nucleotides separat-ing the half-sites can be from 2 to 4 nucleotides. The JAK/STAT pathway is central to many fundamental biologicprocesses and is tightly regulated by several mechanismsalong the signaling cascade, including suppressor of cyto-kine signaling and protein inhibitor of activated STAT, assummarized in Fig 1.2 JAK/STAT dysregulation has beenbeen implicated in many disease processes, including al-lergic inflammation. This review will summarize the roleof STATs in allergic inflammation.

Abbreviations usedCRM: Chromosome region maintenance/exportin

FOXP3: Forkhead box P3

JAK: Janus kinase

LMB: Leptomycin B

NES: Nuclear export signal

SH: SRC homology

SLIM: STAT-interacting LIM protein

SNP: Single nucleotide polymorphism

STAT: Signal transducer and activator of transcription

Treg: Regulatory T cell

529

mailto:Gurjit.Hershey@cchmc.orgmailto:Gurjit.Hershey@cchmc.org

J ALLERGY CLIN IMMUNOL

MARCH 2007

530 Chen and Khurana Hershey

Revie

ws

and

featu

rearticle

s

FIG 1. Overview of STAT signaling pathway and regulation.

OVERVIEW OF STAT PROTEINS

Structure

The STAT protein family has 7 members: STAT1through STAT6, including STAT5A and STAT5B.Recently, a STAT6 homologue (STAT6B), which maybe generated by alternative splicing, was identified.3

STATs are activated in response to distinct stimuli and in-duce the transcription of genes that can elicit diverse bio-logical outcomes. STAT homologs have been identified insimple eukaryotes, suggesting that they arose from a sin-gle gene.4 All STAT proteins share the same overall

structure (Fig 2), including an N-terminal domain, acoiled-coil domain, a DNA-binding domain, a linkerdomain, an SRC homology 2 (SH2) domain, a conservedsingle tyrosine residue that is phosphorylated followingactivation, and a carboxy terminal that facilitates tran-scriptional activation.2 STATs are activated by tyrosinephosphorylation of the conserved tyrosine residue in thetransactivation domain, and this modification serves as amolecular switch that alters their conformation, enablingtheir dimer formation through reciprocal tyrosine phos-phorylation and SH2-domain interactions and specificbinding to DNA. Although some STAT molecules form

J ALLERGY CLIN IMMUNOL

VOLUME 119, NUMBER 3

Chen and Khurana Hershey 531

Revie

ws

and

featu

reart

icle

s

FIG 2. Structure of STAT proteins. a.a., Amino acid; NTD, amino-terminal domain; DBD, DNA-binding domain;

TAD, transactivation domain.

TABLE I. Functions of STAT proteins

Gene

Phenotype

of knockout mice Human deficiency

Dysregulation

in human diseases References

STAT1 Impaired IFN signaling Mycobacterial and viral

diseases

IBD, rheumatoid arthritis, celiac

disease, Alzheimer disease,

multiple sclerosis, ischemic

heart disease, cancers

10, 11, 22, 24-31

STAT2 Impaired IFN signaling IBD, carcinoid tumor 12, 31, 32

STAT3 Embryonic lethal, impaired

IL-2, IL-6, and IL-10 signaling

IBD, psoriasis, multiple

sclerosis, cancers

13, 25, 30, 33, 34

STAT4 Impaired IL-12 signaling COPD, rheumatoid arthritis,

psoriasis, Sezary syndrome

14, 29, 35-37

STAT5A Impaired PRL signaling IBD, cancers, diabetes,

ischemic heart disease

15-18, 23, 27, 30,

38-40

STAT5B Impaired GH signaling GH insensitivity with

immunodeficiency

STAT6 Impaired IL-4 and IL-13

signaling

Asthma, atopic allergic rhinitis,

ischemic heart disease,

Hodgkin lymphoma

19-21, 29, 41-44

IBD, Inflammatory bowel disease; COPD, chronic obstructive pulmonary disease; PRL, prolactin; GH, growth hormone.

homodimers or homotetramers with each other in an un-phosphorylated state, it is the specific conformation oftyrosine-phosphorylated dimers that enables STATs tobind to consensus sequences in target genes.5-9 The diversefunctions of STATs have been elucidated by studies inmouse gene targeting models,10-21 human deficiency,22,23 andassociated human diseases for STAT1,24-31 STAT2,31,32

STAT3,25,30,33,34 STAT4,29,35-37 STAT5,27,30,38-40 andSTAT629,41-44 (Table I).

STAT Phosphorylation

Tyrosine phosphorylation of STATs is initiated predom-inantly by cytokine binding to cell-surface cytokine recep-tors. The intracellular domains of many cytokine receptorsare constitutively associated with JAK tyrosine kinases via

conserved box-1 motifs. There are 4 mammalian JAK

kinases (JAK1, JAK2, JAK3, and Tyk2), which each consist

of 7 conserved JAK homology (JH) domains. JAKs have both

a pseudokinase domain (JH1) and a true catalytic kinase

(JH2), leading to their being named after the mythologic

Roman god Janus who had 2 faces. The other domains,

JH3-JH7, mediate associaton with receptors.45 The JAK-

STAT pathway is critical for the response to cytokines crit-

ical for allergic inflammation, including IL-4 and IL-13.Alternative activation pathways exist for STAT activa-

tion. JAKs can be activated in response to distinct ligands

that bind to G-protein coupled 7-transmembrane recep-tors. Prostaglandins have been reported to activate STATs.Prostaglandin E2 interacts with its nuclear receptor EP1,a G-protein-coupled receptor, to activate STAT3 in

J ALLERGY CLIN IMMUNOL

MARCH 2007

532 Chen and Khurana Hershey

Revie

ws

and

featu

rearticle

s

nucleus.46 The G-protein coupled receptor-mediatedSTAT3 activation requires protein kinase A (PKA),c-Jun N-terminal kinase (JNK), and PI3 kinase (PI3K).47

Angiotensin II and some chemokines, such as CC-chemo-kine ligand 5 (CCL5; also known as RANTES) signal viaG-protein coupled receptors and activate STATs in aJak-dependent manner.48-51 STAT3 and STAT5 can alsobe activated by non-receptor oncogenic tyrosine kinasesthat are of viral origin or are generated by chromosomaltranslocation, such as v-Src and breakpoint clusterregion-Abelson, respectively.52 The activity of STAT3and STAT5 is dysregulated in a variety of human tumors.STAT3 and STAT5 acquire oncogenic potential throughconstitutive tyrosine phosphorylation, and this activityhas been shown to be required to sustain a transformedphenotype. Disruption of STAT3 and STAT5 signaling intransformed cells therefore represents an excellent oppor-tunity for targeted cancer therapy. In contrast to STAT3and STAT5, STAT1 negatively regulates cell proliferationand angiogenesis and thereby inhibits tumor formation.STAT1 and its downstream targets have been shown tobe reduced in a variety of human tumors, and this pathwayis another potential target for cancer therapy.53

In some STATs, the C-terminal region also contains aserine residue that is phosphorylated, and this phospho-rylation has been found to regulate the transcriptionalactivity of STATs.54 Serine phosphorylation was firstreported for STAT1 and STAT3 and mapped to Ser727.55-58 STAT1 and STAT3 serine phosphorylation isrequired for maximal transcriptional activity,59 and serinephosphorylation of STAT C-termini may contribute tothe specificity of signaling.60 Serine phosphorylation ofSTAT1 is independent of the tyrosine phosphorylation, al-though serine kinases may recognize tyrosine-phosphory-lated STAT1 preferentially in response to IFN-g.61

STAT cofactors

Various cytokines and growth factors use overlappingJAKs and STATs to induce their diverse and distinctfunctions. One mechanism by which transcription factorsmediate specificity for the promoters they activate is viainteraction with specific cofactors. Cofactors of DNA-binding transcriptional activators are essential for achiev-ing the threshold level of gene activation required toovercome baseline repressive effects of nucleosomes andother chromatin constituents. The coregulatory mecha-nisms by which STATs assemble transcriptional machin-ery and selectively regulate specific gene expression arenot clear, but coactivators have been shown to be impor-tant for STAT activation. The activation of STAT1requires a DNA replication factor, eukaryotic minichro-mosome maintenance 5 (MCM5).62 The activation ofSTAT3 involves CREB-binding protein (CBP)/p300through acetylation. STAT3 is acetylated at a lysine resi-due in the C-terminal transactivation domain by CBP/p300 and activated for its DNA-binding ability and tran-scriptional activity.63,64 A transcriptional cofactor forSTAT6, collaborator of STAT6 (CoaSt6), was recentlydescribed.65 CoaSt6 interacts with STAT6 in vivo and

amplifies IL-4-induced STAT6-dependent gene expres-sion. Aside from the STATs that are activated via theJAK-STAT pathway, additional transcription factors andcofactors that are activated lead to activation of specificgenes via direct and indirect interactions with STATs.66

STAT nuclear import and export

Nuclear translocation is crucial for the function ofSTATs. The movement of large molecules between thecytoplasm and nucleus is restricted and is a potential targetfor transcriptional regulation by controlling the accessof transcription factors to the nucleus. Because STATactivation is critical to many pathways involved in thedevelopment of allergy and allergic inflammation, regu-lation of STAT nuclear trafficking is a potential target fortherapeutic intervention.

Nuclear localization occurs both at the level of nuclearimport and nuclear export.67 STATs are translocated intonucleus in response to cytokine stimulation to activategene expression and subsequently exported back to thecytoplasm. Thus, nuclear import and export are importantpotential regulatory points. Although the STAT proteinsshare similar structural features, their respective nuclear-cytoplasmic localization is distinctly regulated. The recog-nition signals are amino-acid sequences that function eitheras nuclear-localization signals (NLSs) or nuclear-exportsignals (NESs). These signals can function constitutivelyor conditionally depending on protein modifications(that is, phosphorylation) or association with another pro-tein that can alter the conformation of the protein. Thus,association with different proteins can result in differentlocalization patterns. STAT1 can form a complex withtyrosine-phosphorylated STAT2 and a non-STAT factor,IFN-regulatory factor 9 (IRF9).68 This complex, ISGF3,translocates from the cytoplasm to the nucleus and spe-cifically binds to the IFN-stimulated response element(ISRE) in the promoters of responsive genes. STAT2dimerizes with STAT1 after tyrosine phosphorylationand accumulates in the nucleus only in the presence ofSTAT1.69 STAT2 does not form phosphorylated homo-dimers. STAT1 is also tyrosine phosphorylated in re-sponse to IFN-g and forms a homodimer that binds to adistinct DNA target known as the IFN-g–activated site(GAS). Importin-a5 recognizes tyrosine-phosphorylatedSTAT1 either in the form of IFN-stimulated gene factor3 (ISGF3) or as a homodimer.70 A single leucine residueat position 407 is required for binding to importin-a5and transport into the nucleus.70 Interestingly, the bindingsite on importin-a for the phosphorylated STAT1 dimeris distinct from conventional NLS-containing proteins.52

It has been hypothesized that this would enable a STAT1dimer to bind to importin-a5 that is already occupied withcargo and ensure that STAT1 dimers are readily movedto the nucleus independent of rate-limiting quantitiesof importin-a5. STAT2 does not form phosphorylated ho-modimers; nuclear import depends on heterodimerizationwith STAT1.68,69,71-73

Maintenance of STAT6 activity requires ongoing JAKkinase activity and a continuous cycle of activation,

J ALLERGY CLIN IMMUNOL

VOLUME 119, NUMBER 3

Chen and Khurana Hershey 533

Revie

ws

and

featu

reart

icle

s

deactivation, nuclear export, and reactivation.74 Similarly,nuclear accumulation of STAT1 is transient, and withinhours, the STAT1 protein recycles back to the cyto-plasm.75 STAT5 also undergoes nucleocytoplasmiccycles upon erythropoietin (EPO) stimulation.76 Thenuclear export is often mediated by the leucine-rich nu-clear export signals (NESs) that consist of short sequencesof hydrophobic amino acids with the consensus of LX(1-3)LX(2-3)LXL.

59,77 The NES interacts with chromosomeregion maintenance/exportin 1 (CRM1),78,79 and the in-teraction can be disrupted by antibiotic leptomycin B(LMB).80,81 Both LMB-sensitive and LMB-insensitivenuclear export exists for STAT1 and STAT4.82,83 Thus,non–LMB-sensitive nuclear export pathways for STATsexist, but have not been well defined.

Several NES elements of STAT1 have been re-ported.82,84-86 A conserved leucine-rich NES (amino acids302-314) in the coiled-coil domain of STAT1 is requiredfor STAT1 nuclear export after IFN-g treatment.82 A func-tional NES of STAT1 is located in the DNA-bindingdomain of STAT1 (amino acids 392-413). Interestingly,this region includes the Leu407, which is required fornuclear import of STAT1. Thus, the nuclear import andexport sequences are overlapping and may be counter-regulatory based on the conformation of this region.Dephosphorylation of STAT1 and dissociation fromDNA results in the recognition of NES by CRM1 and nu-clear export of STAT1.85 A leucine-rich NES (amino acids400-410) in the STAT1 DNA-binding domain containsLMB-sensitive nuclear export activity. This NES is notimportant for the nuclear export of unphosphorylatedSTAT1, but it is involved in the nuclear export of tyro-sine-phosphorylated STAT1.86 The nucleocytoplasmicshuttling of unphosphorylated STAT1 is controlled by nu-cleoporins, Nup153 and Nup214, and CRM1-dependentnuclear export.87

Three NES elements were identified in STAT3 (aminoacids 306-318, 404-414, and 524-535).88 The first 2 NEScorrespond to the NES in STAT1, whereas the third isnovel in STAT3. The NES 306-318 is involved in nuclearexport in stimulated cells, whereas NES 404-414 and524-535 are involved in basal nuclear export. The NES201-210, which has been shown possessing nuclear exportactivity for STAT1, does not have any nuclear export ac-tivity for STAT3.88 Constitutive nucleocytoplasmic shut-tling is present for STAT3 in unstimulated cells, and it isindependent of tyrosine phosphorylation.89 The shuttlingof STAT3 is balanced by the nuclear export and importsignals. Unlike STAT1, the C-terminal region of STAT3(amino acids 321-771) contains the nuclear export activ-ity, whereas the N-terminal part (1-320) has the nuclearlocalization signal.89

Various importins mediate the nuclear import ofSTAT3.90,91 The arginine residues in the coiled-coileddomain of STAT3 are involved in both nuclear trans-location and CRM1-mediated STAT3 nuclear exportand activation of STAT3.92 Importin-a3 mediatesSTAT3 nuclear import independent of tyrosinephosphorylation.93

STAT trafficking determines cytokinesensitivity and responses

Clearly, nuclear import and export of STAT areimportant determinants of the response to cytokine, butrecent evidence suggests that modulation of STAT traf-ficking is one mechanism by which cytokine responsesmay be modulated and even fine-tuned. Cytokine sen-sitivity has been found to be determined by the nuclearexport of the relevant STAT proteins.94 The rate of nucle-ocytoplasmic cycling of STATs is a novel mechanism bywhich response to cytokine is determined. Cyotkine re-sponses are affected when nuclear trafficking of STATis diminished. IFN-g production and cell proliferationwere both impaired by the impairment of IL-12–depen-dent STAT4 nuclear translocation.83

Dephosphorylation and proteolyticprocessing of STATs

Dephosphorylation of STATs involve tyrosine phos-phatases. Several types of tyrosine phosphatases havebeen identified to dephosphorylate STAT proteins, in-cluding SH2 domain-containing tyrosine phosphatase 1(SHP1), SHP2, protein tyrosine phosphatase 1B (PTP1B),T cell-protein tyrosine phosphatase (TC-PCP), CD45,PTPeC, dual-specificity phosphatases, and low-molecu-lar-weight protein tyrosine phosphatase.2 PhosphorylatedSTATs dimerize in a parallel way and are subject to de-phosphorylation. However, a recent study revealed duringthe activation-inactivation cycle of STAT1 that the paral-lel dimerized STAT1 proteins not bound to DNA weresubject to a conformational change of their dimer from aparallel to antiparallel arrangement, which is more effi-ciently dephosphorylated.95 This is another potentialmechanism by which STAT signals may be regulated.

In addition to dephosphorylation by tyrosine phos-phatases, proteolytic processing is another important stepin the deactivation and downregulation of STATs. Thedephosphorylation and proteolytic processes coordinateto regulate the deactivation of STAT proteins. Ubiquitin/proteasome-mediated protein degradation is the majorpathway for the inactivation of STAT5A, but in thecytoplasm, tyrosine dephosphorylation is the dominantmechanism of inactivation of STAT5A.96 A ubiquitin E3ligase, STAT-interacting LIM protein (SLIM), was foundto regulate proteosome-mediated protein degradation anddephosphorylation of STAT1 and STAT4. Overexpres-sion of SLIM resulted in decreased STAT1 and STAT4activity, whereas SLIM deficiency led to increasedSTAT1 and STAT4 activity and IFN-g production.97 Inaddition to downregulating STATs through degradativepathways, proteolysis of STATs can also contribute tothe formation of novel STAT isoforms. Isoforms ofSTAT3, STAT5, and STAT6 generated by proteolysishave been reported.98-102 These isoforms are referred asSTATg, whereas the isoforms generated by pre-mRNAalternative splicing are referred as STATb. STATbisoforms have been found for STAT1, STAT3,STAT4, and STAT5.73,103-107 The STAT5b acts as a

J ALLERGY CLIN IMMUNOL

MARCH 2007

534 Chen and Khurana Hershey

Revie

ws

and

featu

rearticle

s

dominant-negative variant of STAT5, whereas the STAT3band STAT4b are not dominant-negative factors. STAT3bactivates specific STAT3 target genes and STAT4b acti-vates specific IL-12–induced gene expression.104,107-111

Some STATb isoforms are involved in disease progressionin acute myeloid leukemia.112 The STAT3g displayed dis-tinct expression comparing to STAT3a and STAT3b dur-ing granulocytic differentiation.99 The STAT5g generatedby protein processing has distinct function in activationof IL-3 target genes.98 Proteolytic processing of STAT6in mast cells generates truncated C-terminal proteins(STAT6g) that lack the transactivation domain, whichcan negatively regulate STAT6 function, decreasingIL-4–induced gene expression.101,102

STAT FUNCTIONS

STATs and regulatory T cells

Regulatory T cells (Tregs) have been characterized as adistinct subset of CD31CD41 T cells constitutively ex-pressing the alpha chain of the high-affinity IL-2 receptor,CD25.113 Recently, a unique transcription factor, forkheadbox P3 (FOXP3), was found to be specifically expressed inmurine and human Tregs.114 Studies have also shown thatectopic expression of FOXP3 in CD41 T cells was suffi-cient to confer suppressive capabilities to CD41CD252

T cells.115 Functionally, CD31CD41FOXP31 Tregsact as natural inhibitors of normal immune responses.Defects in Tregs have been associated with a variety of im-mune pathologies. FOXP3-deficient mice develop intensemultiorgan inflammation that is associated with allergicairway inflammation. The resultant hyperimmunoglobuli-nemia E and eosinophilia observed in these mice can bereversed by concurrent STAT6 deficiency.116

Numerous studies have demonstrated that IL-2 isimportant in the maintenance of Tregs. Neutralizingantibody-mediated IL-2 depletion in mice results in auto-immune diseases associated with reduced numbers ofFOXP3-expressing Tregs in the periphery.117 Disruptionof IL-2 signaling in mice by knocking out IL-2, CD25,IL-2Rb, or STAT5 revealed an essential role for IL-2in the thymic development and peripheral maintenanceof Tregs.118-123 Although IL-2 is not required for FOXP3expression,124 it has been shown to upregulate FOXP3expression in Tregs via activation of STAT3 andSTAT5.125 Natural Tregs constitutively express CD25(IL-2Ra), so they express the complete high-affinity IL-2receptor complex (IL-2Ra, b, and gc) and can presumablyrespond to physiologically low concentrations of IL-2 andeffectively compete away IL-2 binding from naive T cellsto receive IL-2-mediated survival signals.126,127

Activation of STAT5 is a primary mechanism of Tregdevelopment stimulated by IL-2.128 Tregs were reduced inSTAT5A/5B deficient mice, indicating that STAT5 isrequired for the maintenance of tolerance in vivo.118,121

STAT5A has been shown to be involved in the develop-ment of Tregs that modulate TH cells differentiation toTH2 cells.

129 The role of STAT5 is further highlighted

by the recent observation that Tregs are decreased inhuman STAT5B deficiency.130

Cytokine signaling pathways are an integral part ofTreg biology. IL-2 and other gc-dependent cytokines arecritical for the thymic development and peripheral main-tenance of FOXP3-expressing natural Tregs. The signal-ing pathway downstream of IL-2, including STAT5, is animportant potential target for therapeutic interventiondirected at Tregs. Other cytokines, including IL-10 andTGF-b, are important in the development of acquiredTregs.131

STATs and inflammation

Dysregulation of STAT pathways can yield allergicinflammation.132 STAT6 is a key mediator of allergen-induced airway inflammation and plays an essential rolein TH2 cell trafficking, chemokine production, mucus pro-duction, airway eosinophilia, and airway hyperresponsive-ness.133,134 STAT6 induces the expression of numerousgenes involved in allergic inflammatory responses, includingeotaxin-1 and eotaxin-3, arginase I, and P-Selectin.135-138

A recent study on adipocyte fatty acid-binding proteinaP2 showed that it is required in the allergic airway inflam-mation and its expression is induced via STAT6-depen-dent mechanisms.139

The role of STAT6 in the development of allergicinflammation is complicated because both STAT6-depen-dent and STAT6-independent pathways are involved, andSTAT6 can positively or negatively regulate gene expres-sion.140,141 The STAT6-signaling pathway is mainlyinduced by IL-4 or IL-13, but other factors can affectSTAT6 signaling. IFN-g inhibits STAT6-dependent sig-naling and gene expression in human airway epithelialcells.142 Protein kinase C zeta (PKCzeta)2/2 mice showedimpaired tyrosine phosphorylation and nuclear transloca-tion of STAT6 and decreased allergen-induced allergicairway responses.143 STAT6 is essential for the develop-ment of allergic airway inflammation induced by acuteallergen exposure but only partially mediates airwayinflammation in a chronic model.144 Gene targeting stud-ies showed that STAT6-deficient mice were protectedfrom the IL-13–induced pulmonary responses, but devel-oped airway hyperresponsiveness and peribronchial fibro-sis during chronic fungal asthma.145,146 IL-5 has beenreported to reconstitute allergen-induced airway inflam-mation and airway hyperresponsiveness in STAT6-defi-cient mice supporting alternate pathways.147

STAT6 is also involved in other inflammatory orimmune-related diseases. STAT6-mediated TH2 im-munity is critical for the development of autoimmunityin Graves hyperthyroidism.148 STAT6 expression isincreased in vascular smooth muscle cells from coronaryarteries of ischemic heart disease, suggesting a role ofSTAT6-mediated inflammation in atherosclerosis.44 Thedeficiency of STAT6 and CD28 results in chronic ectopar-asite-induced inflammatory skin disease.149

The importance of STAT1 in allergic inflammation wasdemonstrated by the inhibition of allergen-induced airwayinflammation and airway hyperresponsiveness by decoy

J ALLERGY CLIN IMMUNOL

VOLUME 119, NUMBER 3

Chen and Khurana Hershey 535

Revie

ws

and

featu

reart

icle

s

oligonucleotide specific for STAT1.150 STAT3, STAT4,and STAT5 all play important roles in inflammation.STAT3 negatively regulates STAT1-mediated inflam-matory gene activation in response to type I IFNs.151

STAT3 is constitutively activated in intestinal T cellsfrom patients with Crohn’s disease and growth hormonereduces STAT3 activation in Crohn’s colitis.152,153

Conditional knockout of STAT3 in endothelial cells re-vealed that STAT3 is a critical anti-inflammatory mediatorin endothelia.154 Cardiomyocyte-restricted knockout ofSTAT3 results in higher sensitivity to inflammation, in-creased cardiac fibrosis, and age-related heart failure.155

IL-12 and IL-18 attenuate airway hyperresponsivenessthrough STAT4 activation,156 and STAT4 has been shownto modulate allergen-induced chemokine production and air-way hyperresponsiveness.157 Mucosal adenovirus mediatedIFN-g gene transfer attenuated allergen-induced airway in-flammation and airway hyperresponsiveness in an IL-12–and STAT4-dependent manner.158 STAT4 is also involvedin the development of airway inflammation in smokersand patients with chronic obstructive pulmonary disease.35

STAT5A is indispensable in STAT6-independent TH2cell differentiation and allergic airway inflammation.159

STAT5 is critical for IgE-induced mast cell activation asSTAT5-deficient mast cells display decreased IgE-medi-ated degranulation, leukotriene B4 production, cytokinesecretion, and survival signals.160 Reduced colinic STAT5expression may contribute to persistent mucosal inflam-mation in colitis.161

STATs and apoptosis

STATs have been implicated in the regulation ofapoptosis. IFN-g suppresses TNF-related apoptosis in-ducing ligand-mediated apoptosis through JAK-STATpathways.162 STAT1a overexpression promotes apopto-sis with enhanced release of cytochrome c from the mito-chondria and increased caspase-3 activity.163 In contrast,inhibition of STAT3 induces apoptosis in prostate cancercell lines.164 Serine phosphorylation of STAT3 is requiredfor the suppression of apoptosis by the Bcl-2 family mem-ber Mcl-1.165 The function of STAT3 in anti-apoptosis issuppressed by GRIM-19, a death-regulated gene product,which interacts with STAT3 and inhibits STAT3 nucleartranslocation.166 STAT5 is critical for the developmentand survival of mast cells as STAT5A/B-deficient cellsdisplayed enhanced apoptosis.167 Similarly, the expressionof dominant-negative forms of STAT5 in a pre-B cell lineresulted in enhanced apoptosis.168 IL-4 mediates apoptosisof developing mast cells and monocyte/macrophagesthrough a STAT6-dependent mitochondrial pathway.169

STAT POLYMORPHISMS

Most STAT genetic polymorphism studies have focusedon STAT6. Several polymorphisms have been identified inSTAT6 genes. Variation in the dinucleotide (GT) repeat se-quence in exon 1 of the STAT6 gene has been associatedwith atopic asthma and increased total serum IgE level

in a British population.170 Studies done in vitro examiningthe functional significance of this variation showed thatthe GT repeat modulates promoter activity by alteringthe binding stability of nuclear factors.170 In a Caucasiansib-pair study, the GT repeat in exon 1 of STAT6 was as-sociated with eosinophilia and total serum IgE levels,but not with asthma.171 In a Japanese population, theGT repeat polymorphism in exon 1 in combination withhomozygosity for the 2964G allele was significantlyoverrepresented in subjects with allergy.172 However, ina study of Chinese patients with atopic dermatitis, no asso-ciation of the STAT6 GT repeat polymorphism wasfound.173 Specific haplotypes of a polymorphic CA repeatin the proximal promoter region and in the 59 untranslatedregion of STAT6 were found to be associated with asthmain an Indian population.174 A separate study on 6 polymor-phisms of the STAT6 gene in a German population re-vealed significant associations of specific haplotypes andsingle nucleotide polymorphisms (SNPs) with elevated se-rum IgE, specific sensitization, and/or asthma risk.175 InFinnish families with asthma, polymorphisms of STAT6or STAT4 were not found to be associated with asthmaor elevated serum IgE levels.176 In a British patient popu-lation, a STAT6 39 untranslated region polymorphism wasassociated with the risk and severity of nut allergy.177

Cumulatively, there is strong evidence for genetic associa-tions of STATs with atopic disease. The mechanisms bywhich these STAT polymorphisms confer risk for differentatopy phenotypes is not yet clear, although several havebeen found to have functional significance. STAT6 poly-morphisms are also associated with other human diseases.One study showed that the STAT6 G2964A polymorphismis associated with Crohn’s disease in German patients, butother studies did not find this relationship in Dutch orChinese populations.178-181

In addition to STAT6, polymorphisms of STAT3 andSTAT4 have also been studied in atopic disorders.Analysis of STAT3 polymorphisms revealed associationof STAT3 SNPs with lung function (FEV1) in adults andchildren with asthma.182 Among 12 SNPs of STAT4 ana-lyzed, 1 SNP in intron 11 and 2 haplotypes were found tobe associated with Dermatophagoides farninae (Der p)-or Dermatophagoides pteronyssinus (Der f)-specific IgE,suggesting a role for these STAT4 polymorphisms in theproduction of IgE in response to mite allergens inasthma.183 No association of polymorphisms of STAT4with asthma or elevated serum IgE level was identifiedin Finnish families with asthma.176

PHARMACEUTICAL TARGETINGOF JAK-STAT

Progress in our understanding of inflammatory signal-ing pathways has identified new targets, including pathwaysinvolving JAK-STAT. Inhibitors have been developed thatmight be used clinically for inflammatory diseases.184 Ofthe 4 JAKs, JAK3 has been the focus of most interest interms of drug development because of its selective

J ALLERGY CLIN IMMUNOL

MARCH 2007

536 Chen and Khurana Hershey

Revie

ws

and

featu

rearticle

s

FIG 3. Potential pharmaceutical targeting of the STAT-signaling pathway.

expression in T cells and its activation by IL-2. JAK3 iscritical for gc signaling (utilized by IL-2, IL-4, IL-7, IL-9,and IL-15) and constitutively associates with the gc chain.JAK3 deficiency accounts for approximately 7% to 14% ofsevere combined immunodeficiency cases.185-190 Impor-tantly, JAK3 deficiency does not result in widespread plei-otropic defects, so a highly specific JAK3 inhibitor shouldalso have limited and precise effects. An orally availableselective JAK3 antagonist has been developed.191

The drug, CP-690550, has an IC50 of 1 nmol/L191 and isapproximately 30-fold and 100-fold less potent for JAK2and JAK1, respectively. CP-690550 showed remarkableefficacy in the prevention of graft rejection in a primatemodel,191 and the efficacy observed with CP-690550surpassed that obtained with cyclosporine A in the samemodel. CP-690550 potently blocks IL-2 signaling andresponses, but does not effect T-cell receptor signaling.Indeed, the combination of a calcineurin inhibitor, whichwould block signals emanating from the T-cell receptor,and CP-690550 reveal synergistic effects.192 CP-690550did not cause granulocyte or platelet deficiency. Therewas a trend in the reduction of CD81 T cells, but nosignificant decline in total T lymphocytes. CP-690550 iscurrently being evaluated in models of autoimmunity.

IL-4 is a critical cytokine in promoting TH2 differenti-ation and the allergic response. Because IL-4 utilizes thegc chain and JAK3 for signaling, a JAK3 inhibitor wouldbe expected to antagonize IL-4. Thus, a JAK3 antagonistmay be useful in allergic disorders. CP-690550 was alsofound to inhibit delayed-type hypersensitivity, and its ef-fects were reversible when the drug was discontinued.192

IL-9 has been reported to contribute to the developmentof asthma and has been suggested as a potential targetfor asthma treatment.193 Antagonizing the effects of IL-9with a JAK3 antagonist could be of use in treating asthma,although the importance of this cytokine in asthma iscontroversial.194-196 Aside from JAK3, another possibleJAK to target would be Tyk2. Tyk2 is involved in IL-13

signaling and is necessary for the induction of IL-13–mediated goblet cell hyperplasia in the airways.197,198

At present, targeting STATs has met with less successthan targeting JAKs, because it has been simpler toidentify small molecules that interfere with JAK catalyticactivity. However, because of their crucial selectivefunctions, targeting STATs remains an attractive goal.Potential mechanisms to block STAT activity includeblocking their recruitment to cytokine receptors, dimeriza-tion, nuclear import, DNA binding, dephosphorylation, ornuclear export (Fig 3).2

In terms of allergic disease, 2 STATs that might beuseful to target are STAT4 and STAT6.2 These STATs arecrucially important for the differentiation of TH cells. IL-4activates STAT6 and promotes the differentiation of TH2cells that promote allergic responses. Conversely, IL-12activates STAT4 and drives the differentiation of naiveT cells into TH1 cells that produce IFN-g. As discussedabove, constitutive activation of STAT3 and STAT5has been noted in several tumors. Targeting these STATsfor the treatment of cancer is of high interest.199,200

Antagonizing the expression or activation of STAT3induces apoptosis of cancer cells, inhibits angiogenesis,and promotes the elimination of cancer cells by activatingdendritic cells.184 However, STAT3 deficiency is embry-onically lethal.2 The therapeutic window for antagonizingSTAT3 function may be narrow.

Because the JAK-STAT pathway is central to so manyfundamental biologic processes, it is not surprising that theregulation of STAT function is a tightly regulated process.Indeed, several mechanisms have been described thatserve to regulate the JAK-STAT pathway at differentpoints along the cascade, and these regulatory mechanismsare potential targets to modulate STATs.2 The importanceof STATs is further highlighted by their role in themechanisms by which other agents mediate their effects.Cyclooxygenase-2 (COX-2) inhibitors prevent experi-mental allergic encephalomyelitis, a TH1-cell–mediated

J ALLERGY CLIN IMMUNOL

VOLUME 119, NUMBER 3

Chen and Khurana Hershey 537

Revie

ws

and

featu

reart

icle

s

autoimmune disease model of multiple sclerosis, by reduc-ing IL-12 production and decreasing IL-12-induced T-cellresponses, through inhibition of STAT3 and STAT4 tyro-sine phosphorylation.201 The 3-hydroxy-3-methylglutarylcoenzyme A reductase inhibitor, Atorvastatin (Pfizer, NewYork, NY), induces STAT6 phosphorylation and TH2 cy-tokine secretion while inhibiting STAT4 phosphorylationand TH1 cytokine secretion.

202 The direct anti-inflamma-tory effects of statins are achieved by reducing IL-6-induced phosphorylation of STAT3 in hepatocytes.203

Paclitaxel (Myers Squibb Co, New York, NY), a micro-tube stabilizer used in anticancer therapy, significantly de-creases the nuclear translocation of STAT protein inadipocytes without effecting tyrosine phosphorylation.204

Given the central role of the JAK-STAT signaling in bio-logic processes involved in all phases of the immune re-sponse and the successful generation of a selective JAKinhibitor, STATs will continue to be the focus of consider-able attention as potential therapeutics.

CONCLUSION

STAT proteins are critical for many intersecting anddivergent pathways that contribute to allergic inflamma-tion. Their expression, and consequently their impact,is ubiquitous, impacting a variety of cell types critical toallergy including epithelial cells, mast cells, lymphocytes,dendritic cells, and eosinophils. Dysregulation of STATsignaling has been found in human and animal studies ofallergic disease. There is considerable potential of thesepathways as a target for therapeutic intervention. Someprogress has already been made in targeting JAK-STAT;however, considerable work remains for us to fullydelineate the mechanisms by which these molecules areregulated and the optimal targets for intervention.

REFERENCES

1. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcrip-

tional activation in response to IFNs and other extracellular signaling

proteins. Science 1994;264:1415-21.

2. Chen W, Daines MO, Khurana Hershey GK. Turning off signal trans-

ducer and activator of transcription (STAT): the negative regulation of

STAT signaling. J Allergy Clin Immunol 2004;114:476-89; quiz 90.

3. Tang X, Marciano DL, Leeman SE, Amar S. LPS induces the interac-

tion of a transcription factor, LPS-induced TNF-alpha factor, and

STAT6(B) with effects on multiple cytokines. Proc Natl Acad Sci

U S A 2005;102:5132-7.

4. Miyoshi K, Cui Y, Riedlinger G, Robinson P, Lehoczky J, Zon L, et al.

Structure of the mouse Stat 3/5 locus: evolution from Drosophila to

zebrafish to mouse. Genomics 2001;71:150-5.

5. Becker S, Groner B, Muller CW. Three-dimensional structure of the

Stat3b homodimer bound to DNA. Nature 1998;394:145-51.

6. Chen X, Vinkemeier U, Zhao Y, Jeruzalmi D, Darnell JE Jr, Kuriyan J.

Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to

DNA. Cell 1998;93:827-39.

7. Mao X, Ren Z, Parker GN, Sondermann H, Pastorello MA, Wang W,

et al. Structural bases of unphosphorylated STAT1 association and

receptor binding. Mol Cell 2005;17:761-71.

8. Neculai D, Neculai AM, Verrier S, Straub K, Klumpp K, Pfitzner E,

et al. Structure of the unphosphorylated STAT5a dimer. J Biol Chem

2005;280:40782-7.

9. Stancato LF, David M, Carter-Su C, Larner AC, Pratt WB. Preassoci-

ation of STAT1 with STAT2 and STAT3 in separate signalling com-

plexes prior to cytokine stimulation. J Biol Chem 1996;271:4134-7.

10. Durbin JE, Hackenmiller R, Simon MC, Levy DE. Targeted disruption

of the mouse Stat1 gene results in compromised innate immunity to

viral disease. Cell 1996;84:443-50.

11. Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, Dighe AS,

et al. Targeted disruption of the Stat1 gene in mice reveals unexpected

physiologic specificity in the JAK-STAT signaling pathway. Cell 1996;

84:431-42.

12. Park C, Li S, Cha E, Schindler C. Immune response in Stat2 knockout

mice. Immunity 2000;13:795-804.

13. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N,

et al. Targeted disruption of the mouse Stat3 gene leads to early embry-

onic lethality. Proc Natl Acad Sci U S A 1997;94:3801-4.

14. Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses

and enhanced development of Th2 cells in Stat4-deficient mice. Nature

1996;382:174-7.

15. Thierfelder WE, van Deursen JM, Yamamoto K, Tripp RA, Sarawar

SR, Carson RT, et al. Requirement for Stat4 in interleukin-12-mediated

responses of natural killer and T cells. Nature 1996;382:171-4.

16. Nakajima H, Liu XW, Wynshaw-Boris A, Rosenthal LA, Imada K, Fin-

bloom DS, et al. An indirect effect of Stat5a in IL-2-induced prolifera-

tion: a critical role for Stat5a in IL-2-mediated IL-2 receptor alpha chain

induction. Immunity 1997;7:691-701.

17. Feldman GM, Rosenthal LA, Liu X, Hayes MP, Wynshaw-Boris A,

Leonard WJ, et al. STAT5A-deficient mice demonstrate a defect in

granulocyte-macrophage colony-stimulating factor-induced prolifera-

tion and gene expression. Blood 1997;90:1768-76.

18. Imada K, Bloom ET, Nakajima H, Horvath-Arcidiacono JA, Udy GB,

Davey HW, et al. Stat5b is essential for natural killer cell-mediated

proliferation and cytolytic activity. J Exp Med 1998;188:2067-74.

19. Takeda K, Tanaka T, Shi W, Matsumoto M, Minami M, Kashiwamura S,

et al. Essential role of Stat6 in IL-4 signalling. Nature 1996;380:

627-30.

20. Shimoda K, van Deursen J, Sangster MY, Sarawar SR, Carson RT,

Tripp RA, et al. Lack of IL-4-induced Th2 response and IgE class

switching in mice with disrupted Stat6 gene. Nature 1996;380:630-3.

21. Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required

for mediating responses to IL-4 and for development of Th2 cells.

Immunity 1996;4:313-9.

22. Dupuis S, Dargemont C, Fieschi C, Thomassin N, Rosenzweig S,

Harris J, et al. Impairment of mycobacterial but not viral immunity

by a germline human STAT1 mutation. Science 2001;293:300-3.

23. Kofoed EM, Hwa V, Little B, Woods KA, Buckway CK, Tsubaki J,

et al. Growth hormone insensitivity associated with a STAT5b muta-

tion. N Engl J Med 2003;349:1139-47.

24. Kitamura Y, Shimohama S, Ota T, Matsuoka Y, Nomura Y, Taniguchi

T. Alteration of transcription factors NF-kappaB and STAT1 in Alz-

heimer’s disease brains. Neurosci Lett 1997;237:17-20.

25. Frisullo G, Angelucci F, Caggiula M, Nociti V, Iorio R, Patanella AK,

et al. pSTAT1, pSTAT3, and T-bet expression in peripheral blood

mononuclear cells from relapsing-remitting multiple sclerosis patients

correlates with disease activity. J Neurosci Res 2006;84:1027-36.

26. Feng X, Petraglia AL, Chen M, Byskosh PV, Boos MD, Reder AT.

Low expression of interferon-stimulated genes in active multiple sclero-

sis is linked to subnormal phosphorylation of STAT1. J Neuroimmunol

2002;129:205-15.

27. Ng DC, Court NW, dos Remedios CG, Bogoyevitch MA. Activation of

signal transducer and activator of transcription (STAT) pathways in

failing human hearts. Cardiovasc Res 2003;57:333-46.

28. Mazzarella G, MacDonald TT, Salvati VM, Mulligan P, Pasquale L,

Stefanile R, et al. Constitutive activation of the signal transducer and

activator of transcription pathway in celiac disease lesions. Am J Pathol

2003;162:1845-55.

29. Walker JG, Ahern MJ, Coleman M, Weedon H, Papangelis V, Berou-

kas D, et al. Expression of Jak3, STAT1, STAT4, and STAT6 in in-

flammatory arthritis: unique Jak3 and STAT4 expression in dendritic

cells in seropositive rheumatoid arthritis. Ann Rheum Dis 2006;65:

149-56.

30. Hodge DR, Hurt EM, Farrar WL. The role of IL-6 and STAT3 in

inflammation and cancer. Eur J Cancer 2005;41:2502-12.

J ALLERGY CLIN IMMUNOL

MARCH 2007

538 Chen and Khurana Hershey

Revie

ws

and

featu

rearticle

s

31. Zhou Y, Wang S, Gobl A, Oberg K. Interferon alpha induction of

Stat1 and Stat2 and their prognostic significance in carcinoid tumors.

Oncology 2001;60:330-8.

32. Mudter J, Weigmann B, Bartsch B, Kiesslich R, Strand D, Galle PR,

et al. Activation pattern of signal transducers and activators of transcrip-

tion (STAT) factors in inflammatory bowel diseases. Am J Gastroen-

terol 2005;100:64-72.

33. Musso A, Dentelli P, Carlino A, Chiusa L, Repici A, Sturm A, et al.

Signal transducers and activators of transcription 3 signaling pathway:

an essential mediator of inflammatory bowel disease and other forms of

intestinal inflammation. Inflamm Bowel Dis 2005;11:91-8.

34. Gu X, Lundqvist EN, Coates PJ, Thurfjell N, Wettersand E, Nylander

K. Dysregulation of TAp63 mRNA and protein levels in psoriasis.

J Invest Dermatol 2006;126:137-41.

35. Di Stefano A, Caramori G, Capelli A, Gnemmi I, Ricciardolo FL, Oates

T, et al. STAT4 activation in smokers and patients with chronic obstruc-

tive pulmonary disease. Eur Respir J 2004;24:78-85.

36. Showe LC, Fox FE, Williams D, Au K, Niu Z, Rook AH. Depressed

IL-12-mediated signal transduction in T cells from patients with Sezary

syndrome is associated with the absence of IL-12 receptor beta 2 mRNA

and highly reduced levels of STAT4. J Immunol 1999;163:4073-9.

37. Eriksen KW, Lovato P, Skov L, Krejsgaard T, Kaltoft K, Geisler C,

et al. Increased sensitivity to interferon-alpha in psoriatic T cells. J In-

vest Dermatol 2005;125:936-44.

38. Nevalainen MT, Xie J, Torhorst J, Bubendorf L, Haas P, Kononen J,

et al. Signal transducer and activator of transcription-5 activation and

breast cancer prognosis. J Clin Oncol 2004;22:2053-60.

39. Li H, Ahonen TJ, Alanen K, Xie J, LeBaron MJ, Pretlow TG, et al. Ac-

tivation of signal transducer and activator of transcription 5 in human

prostate cancer is associated with high histological grade. Cancer Res

2004;64:4774-82.

40. Han X, Benight N, Osuntokun B, Loesch K, Frank SJ, Denson LA.

Tumour necrosis factor alpha blockade induces an anti-inflammatory

growth hormone signalling pathway in experimental colitis. Gut 2007;56:

73-81.

41. Ghaffar O, Christodoulopoulos P, Lamkhioued B, Wright E, Ihaku D,

Nakamura Y, et al. In vivo expression of signal transducer and activator

of transcription factor 6 (STAT6) in nasal mucosa from atopic allergic

rhinitis: effect of topical corticosteroids. Clin Exp Allergy 2000;30:

86-93.

42. Mullings RE, Wilson SJ, Puddicombe SM, Lordan JL, Bucchieri F,

Djukanovic R, et al. Signal transducer and activator of transcription 6

(STAT-6) expression and function in asthmatic bronchial epithelium.

J Allergy Clin Immunol 2001;108:832-8.

43. Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trumper L, Kapp U,

et al. Signal transducer and activator of transcription 6 is frequently

activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma.

Blood 2002;99:618-26.

44. Satterthwaite G, Francis SE, Suvarna K, Blakemore S, Ward C, Wallace

D, et al. Differential gene expression in coronary arteries from patients

presenting with ischemic heart disease: further evidence for the inflam-

matory basis of atherosclerosis. Am Heart J 2005;150:488-99.

45. Schindler CW. Series introduction. JAK-STAT signaling in human

disease. J Clin Invest 2002;109:1133-7.

46. Han C, Demetris AJ, Stolz DB, Xu L, Lim K, Wu T. Modulation of

Stat3 activation by the cytosolic phospholipase A2a and cyclooxygen-

ase-2-controlled prostaglandin E2 signaling pathway. J Biol Chem

2006;281:24831-46.

47. Liu AM, Lo RK, Wong CS, Morris C, Wise H, Wong YH. Activation

of STAT3 by G alpha(s) distinctively requires protein kinase A, JNK,

and phosphatidylinositol 3-kinase. J Biol Chem 2006;281:35812-25.

48. Marrero MB, Schieffer B, Paxton WG, Heerdt L, Berk BC, Delafon-

taine P, et al. Direct stimulation of Jak/STAT pathway by the angioten-

sin II AT1 receptor. Nature 1995;375:247-50.

49. McWhinney CD, Dostal D, Baker K. Angiotensin II activates Stat5

through Jak2 kinase in cardiac myocytes. J Mol Cell Cardiol 1998;

30:751-61.

50. Mellado M, Rodriguez-Frade JM, Manes S, Martinez AC. Chemokine

signaling and functional responses: the role of receptor dimerization

and TK pathway activation. Annu Rev Immunol 2001;19:397-421.

51. Wong M, Fish EN. RANTES and MIP-1alpha activate stats in T cells.

J Biol Chem 1998;273:309-14.

52. Reich NC, Liu L. Tracking STAT nuclear traffic. Nat Rev Immunol

2006;6:602-12.

53. Klampfer L. Signal transducers and activators of transcription (STATs):

novel targets of chemopreventive and chemotherapeutic drugs. Curr

Cancer Drug Targets 2006;6:107-21.

54. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene

2000;19:2628-37.

55. Eilers A, Georgellis D, Klose B, Schindler C, Ziemiecki A, Harpur AG,

et al. Differentiation-regulated serine phosphorylation of STAT1 pro-

motes GAF activation in macrophages. Mol Cell Biol 1995;15:3579-86.

56. Wen Z, Zhong Z, Darnell JE Jr. Maximal activation of transcription by

Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell

1995;82:241-50.

57. Zhang X, Blenis J, Li HC, Schindler C, Chen-Kiang S. Requirement of

serine phosphorylation for formation of STAT-promoter complexes.

Science 1995;267:1990-4.

58. Wen Z, Darnell JE Jr. Mapping of Stat3 serine phosphorylation to a single

residue (727) and evidence that serine phosphorylation has no influence

on DNA binding of Stat1 and Stat3. Nucleic Acids Res 1997;25:2062-7.

59. Wen W, Meinkoth JL, Tsien RY, Taylor SS. Identification of a signal

for rapid export of proteins from the nucleus. Cell 1995;82:463-73.

60. Kovarik P, Mangold M, Ramsauer K, Heidari H, Steinborn R, Zotter A,

et al. Specificity of signaling by STAT1 depends on SH2 and C-termi-

nal domains that regulate Ser727 phosphorylation, differentially affect-

ing specific target gene expression. Embo J 2001;20:91-100.

61. Kovarik P, Stoiber D, Novy M, Decker T. Stat1 combines signals

derived from IFN-gamma and LPS receptors during macrophage acti-

vation. Embo J 1998;17:3660-8.

62. Snyder M, He W, Zhang JJ. The DNA replication factor MCM5 is

essential for Stat1-mediated transcriptional activation. Proc Natl Acad

Sci U S A 2005;102:14539-44.

63. Ray S, Boldogh I, Brasier AR. STAT3 NH2-terminal acetylation is

activated by the hepatic acute-phase response and required for IL-6

induction of angiotensinogen. Gastroenterology 2005;129:1616-32.

64. Wang R, Cherukuri P, Luo J. Activation of Stat3 sequence-specific

DNA binding and transcription by p300/CREB-binding protein-medi-

ated acetylation. J Biol Chem 2005;280:11528-34.

65. Goenka S, Boothby M. Selective potentiation of Stat-dependent gene

expression by collaborator of Stat6 (CoaSt6), a transcriptional cofactor.

Proc Natl Acad Sci U S A 2006;103:4210-5.

66. van Boxel-Dezaire AH, Rani MR, Stark GR. Complex modulation of

cell type-specific signaling in response to type I interferons. Immunity

2006;25:361-72.

67. Ullman KS, Powers MA, Forbes DJ. Nuclear export receptors: from

importin to exportin. Cell 1997;90:967-70.

68. Veals SA, Schindler C, Leonard D, Fu XY, Aebersold R, Darnell JE Jr,

et al. Subunit of an alpha-interferon-responsive transcription factor is

related to interferon regulatory factor and Myb families of DNA-bind-

ing proteins. Mol Cell Biol 1992;12:3315-24.

69. Banninger G, Reich NC. STAT2 nuclear trafficking. J Biol Chem 2004;

279:39199-206.

70. McBride KM, Banninger G, McDonald C, Reich NC. Regulated

nuclear import of the STAT1 transcription factor by direct binding of

importin-alpha. Embo J 2002;21:1754-63.

71. Schindler C, Fu XY, Improta T, Aebersold R, Darnell JE Jr. Proteins of

transcription factor ISGF-3: one gene encodes the 91-and 84-kDa

ISGF-3 proteins that are activated by interferon alpha. Proc Natl

Acad Sci U S A 1992;89:7836-9.

72. Schindler C, Shuai K, Prezioso VR, Darnell JE Jr. Interferon-dependent

tyrosine phosphorylation of a latent cytoplasmic transcription factor.

Science 1992;257:809-13.

73. Shuai K, Stark GR, Kerr IM, Darnell JE Jr. A single phosphotyrosine

residue of Stat91 required for gene activation by interferon-gamma.

Science 1993;261:1744-6.

74. Andrews RP, Ericksen MB, Cunningham CM, Daines MO, Hershey

GK. Analysis of the life cycle of stat6. Continuous cycling of STAT6

is required for IL-4 signaling. J Biol Chem 2002;277:36563-9.

75. Koster M, Hauser H. Dynamic redistribution of STAT1 protein in IFN sig-

naling visualized by GFP fusion proteins. Eur J Biochem 1999;260:137-44.

76. Swameye I, Muller TG, Timmer J, Sandra O, Klingmuller U. Identifica-

tion of nucleocytoplasmic cycling as a remote sensor in cellular signaling

by databased modeling. Proc Natl Acad Sci U S A 2003;100:1028-33.

J ALLERGY CLIN IMMUNOL

VOLUME 119, NUMBER 3

Chen and Khurana Hershey 539

Revie

ws

and

featu

reart

icle

s

77. Fischer U, Huber J, Boelens WC, Mattaj IW, Luhrmann R. The HIV-1

Rev activation domain is a nuclear export signal that accesses an export

pathway used by specific cellular RNAs. Cell 1995;82:475-83.

78. Fornerod M, Ohno M, Yoshida M, Mattaj IW. CRM1 is an export re-

ceptor for leucine-rich nuclear export signals. Cell 1997;90:1051-60.

79. Stade K, Ford CS, Guthrie C, Weis K. Exportin 1 (Crm1p) is an essen-

tial nuclear export factor. Cell 1997;90:1041-50.

80. Wolff B, Sanglier JJ, Wang Y. Leptomycin B is an inhibitor of nuclear

export: inhibition of nucleo-cytoplasmic translocation of the human

immunodeficiency virus type 1 (HIV-1) Rev protein and Rev-dependent

mRNA. Chem Biol 1997;4:139-47.

81. Kudo N, Wolff B, Sekimoto T, Schreiner EP, Yoneda Y, Yanagida M,

et al. Leptomycin B inhibition of signal-mediated nuclear export by

direct binding to CRM1. Exp Cell Res 1998;242:540-7.

82. Begitt A, Meyer T, van Rossum M, Vinkemeier U. Nucleocytoplasmic

translocation of Stat1 is regulated by a leucine-rich export signal in the

coiled-coil domain. Proc Natl Acad Sci U S A 2000;97:10418-23.

83. Toyoda H, Ido M, Hayashi T, Gabazza EC, Suzuki K, Bu J, et al. Im-

pairment of IL-12-dependent STAT4 nuclear translocation in a patient

with recurrent Mycobacterium avium infection. J Immunol 2004;172:

3905-12.

84. Mowen K, David M. Regulation of STAT1 nuclear export by Jak1. Mol

Cell Biol 2000;20:7273-81.

85. McBride KM, McDonald C, Reich NC. Nuclear export signal located

within theDNA-binding domain of the STAT1transcription factor.

Embo J 2000;19:6196-206.

86. Meyer T, Begitt A, Lodige I, van Rossum M, Vinkemeier U. Constitu-

tive and IFN-gamma-induced nuclear import of STAT1 proceed

through independent pathways. Embo J 2002;21:344-54.

87. Marg A, Shan Y, Meyer T, Meissner T, Brandenburg M, Vinkemeier U.

Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and

CRM1-dependent nuclear export control the subcellular distribution of

latent Stat1. J Cell Biol 2004;165:823-33.

88. Bhattacharya S, Schindler C. Regulation of Stat3 nuclear export. J Clin

Invest 2003;111:553-9.

89. Pranada AL, Metz S, Herrmann A, Heinrich PC, Muller-Newen G. Real

time analysis of STAT3 nucleocytoplasmic shuttling. J Biol Chem

2004;279:15114-23.

90. Ma J, Cao X. Regulation of Stat3 nuclear import by importin alpha5

and importin alpha7 via two different functional sequence elements.

Cell Signal 2006;18:1117-26.

91. Ushijima R, Sakaguchi N, Kano A, Maruyama A, Miyamoto Y, Seki-

moto T, et al. Extracellular signal-dependent nuclear import of STAT3

is mediated by various importin alphas. Biochem Biophys Res

Commun 2005;330:880-6.

92. Sato N, Tsuruma R, Imoto S, Sekine Y, Muromoto R, Sugiyama K,

et al. Nuclear retention of STAT3 through the coiled-coil domain

regulates its activity. Biochem Biophys Res Commun 2005;336:

617-24.

93. Liu L, McBride KM, Reich NC. STAT3 nuclear import is independent

of tyrosine phosphorylation and mediated by importin-alpha3. Proc

Natl Acad Sci U S A 2005;102:8150-5.

94. Lodige I, Marg A, Wiesner B, Malecova B, Oelgeschlager T, Vinkeme-

ier U. Nuclear export determines the cytokine sensitivity of STAT tran-

scription factors. J Biol Chem 2005;280:43087-99.

95. Zhong M, Henriksen MA, Takeuchi K, Schaefer O, Liu B, ten Hoeve J,

et al. Implications of an antiparallel dimeric structure of nonphosphory-

lated STAT1 for the activation-inactivation cycle. Proc Natl Acad Sci

U S A 2005;102:3966-71.

96. Chen Y, Dai X, Haas AL, Wen R, Wang D. Proteasome-dependent

down-regulation of activated Stat5A in the nucleus. Blood 2006;108:

566-74.

97. Tanaka T, Soriano MA, Grusby MJ. SLIM is a nuclear ubiquitin E3 ligase

that negatively regulates STAT signaling. Immunity 2005;22:729-36.

98. Azam M, Lee C, Strehlow I, Schindler C. Functionally distinct isoforms

of STAT5 are generated by protein processing. Immunity 1997;6:

691-701.

99. Hevehan DL, Miller WM, Papoutsakis ET. Differential expression and

phosphorylation of distinct STAT3 proteins during granulocytic differ-

entiation. Blood 2002;99:1627-37.

100. Kato T, Sakamoto E, Kutsuna H, Kimura-Eto A, Hato F, Kitagawa S.

Proteolytic conversion of STAT3alpha to STAT3gamma in human

neutrophils: role of granule-derived serine proteases. J Biol Chem

2004;279:31076-80.

101. Shelburne CP, Piekorz RP, Bouton LA, Chong HJ, Ryan JJ. Mast

cell-restricted p70 Stat6 isoform is a product of selective proteolysis.

Cytokine 2002;19:218-27.

102. Suzuki K, Nakajima H, Kagami S, Suto A, Ikeda K, Hirose K, et al.

Proteolytic processing of Stat6 signaling in mast cells as a negative

regulatory mechanism. J Exp Med 2002;196:27-38.

103. Caldenhoven E, van Dijk TB, Solari R, Armstrong J, Raaijmakers JA,

Lammers JW, et al. STAT3beta, a splice variant of transcription factor

STAT3, is a dominant negative regulator of transcription. J Biol Chem

1996;271:13221-7.

104. Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, et al. Dis-

tinct requirements for the naturally occurring splice forms Stat4alpha

and Stat4beta in IL-12 responses. Embo J 2003;22:4237-48.

105. Schaefer TS, Sanders LK, Nathans D. Cooperative transcriptional activity

of Jun and Stat3 beta, a short form of Stat3. Proc Natl Acad Sci U S A

1995;92:9097-101.

106. Schaefer TS, Sanders LK, Park OK, Nathans D. Functional differences

between Stat3alpha and Stat3beta. Mol Cell Biol 1997;17:5307-16.

107. Wang D, Stravopodis D, Teglund S, Kitazawa J, Ihle JN. Naturally oc-

curring dominant negative variants of Stat5. Mol Cell Biol 1996;16:

6141-8.

108. Ilaria RL Jr, Hawley RG, Van Etten RA. Dominant negative mutants

implicate STAT5 in myeloid cell proliferation and neutrophil differen-

tiation. Blood 1999;93:4154-66.

109. Lokuta MA, McDowell MA, Paulnock DM. Identification of an addi-

tional isoform of STAT5 expressed in immature macrophages. J Immu-

nol 1998;161:1594-7.

110. Maritano D, Sugrue ML, Tininini S, Dewilde S, Strobl B, Fu X, et al.

The STAT3 isoforms alpha and beta have unique and specific functions.

Nat Immunol 2004;5:401-9.

111. Mui AL, Wakao H, Kinoshita T, Kitamura T, Miyajima A. Suppression

of interleukin-3-induced gene expression by a C-terminal truncated

Stat5: role of Stat5 in proliferation. Embo J 1996;15:2425-33.

112. Xia Z, Sait SN, Baer MR, Barcos M, Donohue KA, Lawrence D, et al.

Truncated STAT proteins are prevalent at relapse of acute myeloid

leukemia. Leuk Res 2001;25:473-82.

113. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic

self-tolerance maintained by activated T cells expressing IL-2

receptor alpha-chains (CD25). Breakdown of a single mechanism of

self-tolerance causes various autoimmune diseases. J Immunol 1995;

155:1151-64.

114. Sakaguchi S. Naturally arising CD41 regulatory T cells for immuno-logic self-tolerance and negative control of immune responses. Annu

Rev Immunol 2004;22:531-62.

115. Refaeli Y, Van Parijs L, London CA, Tschopp J, Abbas AK. Biochem-

ical mechanisms of IL-2-regulated Fas-mediated T cell apoptosis.

Immunity 1998;8:615-23.

116. Lin W, Truong N, Grossman WJ, Haribhai D, Williams CB, Wang J,

et al. Allergic dysregulation and hyperimmunoglobulinemia E in

Foxp3 mutant mice. J Allergy Clin Immunol 2005;116:1106-15.

117. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic mainte-

nance of natural Foxp3(1) CD25(1) CD4(1) regulatory T cells byinterleukin (IL)-2 and induction of autoimmune disease by IL-2 neutral-

ization. J Exp Med 2005;201:723-35.

118. Antov A, Yang L, Vig M, Baltimore D, Van Parijs L. Essential role for

STAT5 signaling in CD251CD41 regulatory T cell homeostasis andthe maintenance of self-tolerance. J Immunol 2003;171:3435-41.

119. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcer-

ative colitis-like disease in mice with a disrupted interleukin-2 gene.

Cell 1993;75:253-61.

120. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I. Development

and function of T cells in mice rendered interleukin-2 deficient by

gene targeting. Nature 1991;352:621-4.

121. Snow JW, Abraham N, Ma MC, Herndier BG, Pastuszak AW, Gold-

smith MA. Loss of tolerance and autoimmunity affecting multiple

organs in STAT5A/5B-deficient mice. J Immunol 2003;171:5042-50.

122. Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E,

Matsuyama T, et al. Deregulated T cell activation and autoimmu-

nity in mice lacking interleukin-2 receptor beta. Science 1995;268:

1472-6.

J ALLERGY CLIN IMMUNOL

MARCH 2007

540 Chen and Khurana Hershey

Revie

ws

and

featu

rearticle

s

123. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleu-

kin-2 receptor alpha chain regulates the size and content of the periph-

eral lymphoid compartment. Immunity 1995;3:521-30.

124. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for

interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol

2005;6:1142-51.

125. Zorn E, Nelson EA, Mohseni M, Porcheray F, Kim H, Litsa D, et al. IL-2

regulates FOXP3 expression in human CD41CD251 regulatory T cellsthrough a STAT-dependent mechanism and induces the expansion of

these cells in vivo. Blood 2006;108:1571-9.

126. Barthlott T, Moncrieffe H, Veldhoen M, Atkins CJ, Christensen J,

O’Garra A, et al. CD251 CD41 T cells compete with naive CD41T cells for IL-2 and exploit it for the induction of IL-10 production.

Int Immunol 2005;17:279-88.

127. de la Rosa M, Rutz S, Dorninger H, Scheffold A. Interleukin-2 is essen-

tial for CD41CD251 regulatory T cell function. Eur J Immunol 2004;34:2480-8.

128. Burchill MA, Goetz CA, Prlic M, O’Neil JJ, Harmon IR, Bensinger SJ,

et al. Distinct effects of STAT5 activation on CD41 and CD81 T cellhomeostasis: development of CD41CD251 regulatory T cells versusCD81 memory T cells. J Immunol 2003;171:5853-64.

129. Kagami S, Nakajima H, Suto A, Hirose K, Suzuki K, Morita S, et al.

Stat5a regulates T helper cell differentiation by several distinct mecha-

nisms. Blood 2001;97:2358-65.

130. Cohen AC, Nadeau KC, Tu W, Hwa V, Dionis K, Bezrodnik L, et al.

Cutting edge: decreased accumulation and regulatory function of CD41CD25(high) T cells in human STAT5b deficiency. J Immunol 2006;

177:2770-4.

131. Wan YY, Flavell RA. The roles for cytokines in the generation and

maintenance of regulatory T cells. Immunol Rev 2006;212:114-30.

132. Sampath D, Castro M, Look DC, Holtzman MJ. Constitutive activation

of an epithelial signal transducer and activator of transcription (STAT)

pathway in asthma. J Clin Invest 1999;103:1353-61.

133. Akimoto T, Numata F, Tamura M, Takata Y, Higashida N, Takashi T,

et al. Abrogation of bronchial eosinophilic inflammation and airway

hyperreactivity in signal transducers and activators of transcription

(STAT)6-deficient mice. J Exp Med 1998;187:1537-42.

134. Mathew A, MacLean JA, DeHaan E, Tager AM, Green FH, Luster AD.

Signal transducer and activator of transcription 6 controls chemokine

production and T helper cell type 2 cell trafficking in allergic pulmonary

inflammation. J Exp Med 2001;193:1087-96.

135. Hoeck J, Woisetschlager M. Activation of eotaxin-3/CCLl26 gene ex-

pression in human dermal fibroblasts is mediated by STAT6. J Immunol

2001;167:3216-22.

136. Hoeck J, Woisetschlager M. STAT6 mediates eotaxin-1 expression in

IL-4 or TNF-alpha-induced fibroblasts. J Immunol 2001;166:4507-15.

137. Yang M, Rangasamy D, Matthaei KI, Frew AJ, Zimmmermann N, Ma-

halingam S, et al. Inhibition of arginase I activity by RNA interference

attenuates IL-13-induced airways hyperresponsiveness. J Immunol

2006;177:5595-603.

138. Miyazaki Y, Satoh T, Nishioka K, Yokozeki H. STAT-6-mediated

control of P-selectin by substance P and interleukin-4 in human dermal

endothelial cells. Am J Pathol 2006;169:697-707.

139. Shum BO, Mackay CR, Gorgun CZ, Frost MJ, Kumar RK, Hotamisligil

GS, et al. The adipocyte fatty acid-binding protein aP2 is required in

allergic airway inflammation. J Clin Invest 2006;116:2183-92.

140. Zimmermann N, Mishra A, King NE, Fulkerson PC, Doepker MP, Ni-

kolaidis NM, et al. Transcript signatures in experimental asthma: iden-

tification of STAT6-dependent and -independent pathways. J Immunol

2004;172:1815-24.

141. Fulkerson PC, Zimmermann N, Hassman LM, Finkelman FD, Roth-

enberg ME. Pulmonary chemokine expression is coordinately regu-

lated by STAT1, STAT6, and IFN-gamma. J Immunol 2004;173:

7565-74.

142. Heller NM, Matsukura S, Georas SN, Boothby MR, Rothman PB, Stel-

lato C, et al. Interferon-gamma inhibits STAT6 signal transduction and

gene expression in human airway epithelial cells. Am J Respir Cell Mol

Biol 2004;31:573-82.

143. Martin P, Villares R, Rodriguez-Mascarenhas S, Zaballos A, Leitges M,

Kovac J, et al. Control of T helper 2 cell function and allergic airway

inflammation by PKCzeta. Proc Natl Acad Sci U S A 2005;102:

9866-71.

144. Trifilieff A, El-Hasim A, Corteling R, Owen CE. Abrogation of lung

inflammation in sensitized Stat6-deficient mice is dependent on the

allergen inhalation procedure. Br J Pharmacol 2000;130:1581-8.

145. Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z,

et al. Direct effects of interleukin-13 on epithelial cells cause airway

hyperreactivity and mucus overproduction in asthma. Nat Med 2002;

8:885-9.

146. Blease K, Schuh JM, Jakubzick C, Lukacs NW, Kunkel SL, Joshi BH,

et al. Stat6-deficient mice develop airway hyperresponsiveness and per-

ibronchial fibrosis during chronic fungal asthma. Am J Pathol 2002;

160:481-90.

147. Tomkinson A, Kanehiro A, Rabinovitch N, Joetham A, Cieslewicz G,

Gelfand EW. The failure of STAT6-deficient mice to develop airway

eosinophilia and airway hyperresponsiveness is overcome by interleu-

kin-5. Am J Respir Crit Care Med 1999;160:1283-91.

148. Land KJ, Moll JS, Kaplan MH, Seetharamaiah GS. Signal transducer

and activator of transcription (Stat)-6-dependent, but not Stat4-depen-

dent, immunity is required for the development of autoimmunity in

Graves’ hyperthyroidism. Endocrinology 2004;145:3724-30.

149. Liu Q, Arseculeratne C, Liu Z, Whitmire J, Grusby MJ, Finkelman FD,

et al. Simultaneous deficiency in CD28 and STAT6 results in chronic

ectoparasite-induced inflammatory skin disease. Infect Immun 2004;

72:3706-15.

150. Quarcoo D, Weixler S, Groneberg D, Joachim R, Ahrens B, Wagner

AH, et al. Inhibition of signal transducer and activator of transcription

1 attenuates allergen-induced airway inflammation and hyperreactivity.

J Allergy Clin Immunol 2004;114:288-95.

151. Ho HH, Ivashkiv LB. Role of STAT3 in type I interferon responses.

Negative regulation of STAT1-dependent inflammatory gene activation.

J Biol Chem 2006;281:14111-8.

152. Han X, Sosnowska D, Bonkowski EL, Denson LA. Growth hormone

inhibits signal transducer and activator of transcription 3 activation

and reduces disease activity in murine colitis. Gastroenterology 2005;

129:185-203.

153. Lovato P, Brender C, Agnholt J, Kelsen J, Kaltoft K, Svejgaard A, et al.

Constitutive STAT3 activation in intestinal T cells from patients with

Crohn’s disease. J Biol Chem 2003;278:16777-81.

154. Kano A, Wolfgang MJ, Gao Q, Jacoby J, Chai GX, Hansen W, et al.

Endothelial cells require STAT3 for protection against endotoxin-

induced inflammation. J Exp Med 2003;198:1517-25.

155. Jacoby JJ, Kalinowski A, Liu MG, Zhang SS, Gao Q, Chai GX, et al.

Cardiomyocyte-restricted knockout of STAT3 results in higher sensitiv-

ity to inflammation, cardiac fibrosis, and heart failure with advanced

age. Proc Natl Acad Sci U S A 2003;100:12929-34.

156. Matsubara S, Takeda K, Kodama T, Joetham A, Miyahara N, Koya T,

et al. IL-2 and IL-18 Attenuation of Airway Hyperresponsiveness Re-

quires STAT4, Interferon-[gamma], and NK Cells. Am J Respir Cell

Mol Biol 2006;36:324-32.

157. Raman K, Kaplan MH, Hogaboam CM, Berlin A, Lukacs NW. STAT4

signal pathways regulate inflammation and airway physiology changes

in allergic airway inflammation locally via alteration of chemokines.

J Immunol 2003;170:3859-65.

158. Behera AK, Kumar M, Lockey RF, Mohapatra SS. Adenovirus-medi-

ated interferon gamma gene therapy for allergic asthma: involvement

of interleukin 12 and STAT4 signaling. Hum Gene Ther 2002;13:

1697-709.

159. Takatori H, Nakajima H, Hirose K, Kagami S, Tamachi T, Suto A, et al.

Indispensable role of Stat5a in Stat6-independent Th2 cell differentia-

tion and allergic airway inflammation. J Immunol 2005;174:3734-40.

160. Barnstein BO, Li G, Wang Z, Kennedy S, Chalfant C, Nakajima H,

et al. Stat5 expression is required for IgE-mediated mast cell function.

J Immunol 2006;177:3421-6.

161. Han X, Benight N, Osuntokun B, Loesch K, Frank S, Denson L.

Tumour necrosis factor [alpha] blockade induces an anti-inflammatory

growth hormone signalling pathway in experimental colitis. Gut

2007;56:73-81.

162. Tamai M, Kawakami A, Tanaka F, Miyashita T, Nakamura H, Iwanaga

N, et al. Significant inhibition of TRAIL-mediated fibroblast-like syno-

vial cell apoptosis by IFN-gamma through JAK/STAT pathway by

translational regulation. J Lab Clin Med 2006;147:182-90.

163. Balasubramanian A, Ganju RK, Groopman JE. Signal transducer and

activator of transcription factor 1 mediates apoptosis induced by

J ALLERGY CLIN IMMUNOL

VOLUME 119, NUMBER 3

Chen and Khurana Hershey 541

Revie

ws

and

featu

reart

icle

s

hepatitis C virus and HIV envelope proteins in hepatocytes. J Infect Dis

2006;194:670-81.

164. Barton BE, Murphy TF, Shu P, Huang HF, Meyenhofer M, Barton A.

Novel single-stranded oligonucleotides that inhibit signal transducer

and activator of transcription 3 induce apoptosis in vitro and in vivo

in prostate cancer cell lines. Mol Cancer Ther 2004;3:1183-91.

165. Liu H, Ma Y, Cole SM, Zander C, Chen KH, Karras J, et al. Serine

phosphorylation of STAT3 is essential for Mcl-1 expression and

macrophage survival. Blood 2003;102:344-52.

166. Lufei C, Ma J, Huang G, Zhang T, Novotny-Diermayr V, Ong CT, et al.

GRIM-19, a death-regulatory gene product, suppresses Stat3 activity

via functional interaction. Embo J 2003;22:1325-35.

167. Shelburne CP, McCoy ME, Piekorz R, Sexl V, Roh KH, Jacobs-Helber

SM, et al. Stat5 expression is critical for mast cell development and

survival. Blood 2003;102:1290-7.

168. Lanvin O, Gouilleux F, Mullie C, Maziere C, Fuentes V, Bissac E, et al.

Interleukin-7 induces apoptosis of 697 pre-B cells expressing dominant-

negative forms of STAT5: evidence for caspase-dependent and -inde-

pendent mechanisms. Oncogene 2004;23:3040-7.

169. Bailey DP, Kashyap M, Mirmonsef P, Bouton LA, Domen J, Zhu J,

et al. Interleukin-4 elicits apoptosis of developing mast cells via a

Stat6-dependent mitochondrial pathway. Exp Hematol 2004;32:52-9.

170. Gao PS, Heller NM, Walker W, Chen CH, Moller M, Plunkett B, et al.

Variation in dinucleotide (GT) repeat sequence in the first exon of the

STAT6 gene is associated with atopic asthma and differentially regu-

lates the promoter activity in vitro. J Med Genet 2004;41:535-9.

171. Duetsch G, Illig T, Loesgen S, Rohde K, Klopp N, Herbon N, et al.

STAT6 as an asthma candidate gene: polymorphism-screening, associ-

ation and haplotype analysis in a Caucasian sib-pair study. Hum Mol

Genet 2002;11:613-21.

172. Tamura K, Suzuki M, Arakawa H, Tokuyama K, Morikawa A. Linkage

and association studies of STAT6 gene polymorphisms and allergic dis-

eases. Int Arch Allergy Immunol 2003;131:33-8.

173. Chang YT, Lee WR, Yu CW, Liu HN, Lin MW, Huang CH, et al. No

association of cytokine gene polymorphisms in Chinese patients with

atopic dermatitis. Clin Exp Dermatol 2006;31:419-23.

174. Nagarkatti R, B-Rao C, Vijayan V, Sharma SK, Ghosh B. Signal trans-

ducer and activator of transcription 6 haplotypes and asthma in the

Indian population. Am J Respir Cell Mol Biol 2004;31:317-21.

175. Weidinger S, Klopp N, Wagenpfeil S, Rummler L, Schedel M, Kabesch M,

et al. Association of a STAT 6 haplotype with elevated serum IgE levels in

a population based cohort of white adults. J Med Genet 2004;41:658-63.

176. Pykalainen M, Kinos R, Valkonen S, Rydman P, Kilpelainen M, Laiti-

nen LA, et al. Association analysis of common variants of STAT6,

GATA3, and STAT4 to asthma and high serum IgE phenotypes.

J Allergy Clin Immunol 2005;115:80-7.

177. Amoli MM, Hand S, Hajeer AH, Jones KP, Rolf S, Sting C, et al.

Polymorphism in the STAT6 gene encodes risk for nut allergy. Genes

Immun 2002;3:220-4.

178. Klein W, Tromm A, Folwaczny C, Hagedorn M, Duerig N, Epplen J,

et al. The G2964A polymorphism of the STAT6 gene in inflammatory

bowel disease. Dig Liver Dis 2005;37:159-61.

179. de Jong DJ, Franke B, Naber AH, Willemen JJ, Heister AJ, Brunner

HG, et al. No evidence for involvement of IL-4R and CD11B from

the IBD1 region and STAT6 in the IBD2 region in Crohn’s disease.

Eur J Hum Genet 2003;11:884-7.

180. Xia B, Crusius JB, Wu J, Zwiers A, van Bodegraven AA, Pena AS. Sig-

nal transducer and activator of transcription 6 gene G2964A polymor-

phism and inflammatory bowel disease. Clin Exp Immunol 2003;131:

446-50.

181. Zhu J, Xia B, Guo Q, Cheng H, Li J, Ye M, et al. Distribution of signal

transducer and activator of transcription 6 gene G2964A polymorphism

in Chinese patients with ulcerative colitis. J Gastroenterol Hepatol

2006;21:1854-7.

182. Litonjua AA, Tantisira KG, Lake S, Lazarus R, Richter BG, Gabriel S,

et al. Polymorphisms in signal transducer and activator of transcription

3 and lung function in asthma. Respir Res 2005;6:52.

183. Park BL, Cheong HS, Kim LH, Choi YH, Namgoong S, Park HS,

et al. Association analysis of signal transducer and activator of

transcription 4 (STAT4) polymorphisms with asthma. J Hum Genet

2005;50:133-8.

184. O’Shea JJ, Pesu M, Borie DC, Changelian PS. A new modality for

immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug

Discov 2004;3:555-64.

185. Candotti F, Oakes SA, Johnston JA, Giliani S, Schumacher RF, Mella

P, et al. Structural and functional basis for JAK3-deficient severe

combined immunodeficiency. Blood 1997;90:3996-4003.

186. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, et al.

Mutations of Jak-3 gene in patients with autosomal severe combined

immune deficiency (SCID). Nature 1995;377:65-8.

187. Mella P, Schumacher RF, Cranston T, de Saint Basile G, Savoldi G,

Notarangelo LD. Eleven novel JAK3 mutations in patients with severe

combined immunodeficiency-including the first patients with mutations

in the kinase domain. Hum Mutat 2001;18:355-6.

188. Notarangelo LD, Mella P, Jones A, de Saint Basile G, Savoldi G, Cran-

ston T, et al. Mutations in severe combined immune deficiency (SCID)

due to JAK3 deficiency. Hum Mutat 2001;18:255-63.

189. Roberts JL, Lengi A, Brown SM, Chen M, Zhou YJ, O’Shea JJ, et al.

Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular

analyses of 10 patients and outcomes of stem cell transplantation. Blood

2004;103:2009-18.

190. Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ,

et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in

lymphoid development. Science 1995;270:797-800.

191. Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin

WH, et al. Prevention of organ allograft rejection by a specific Janus

kinase 3 inhibitor. Science 2003;302:875-8.

192. Kudlacz E, Perry B, Sawyer P, Conklyn M, McCurdy S, Brissette W,

et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppres-

sive agent in various murine models. Am J Transplant 2004;4:51-7.

193. McNamara PS, Smyth RL. Interleukin-9 as a possible therapeutic target

in both asthma and chronic obstructive airways disease. Drug News

Perspect 2005;18:615-21.

194. McMillan SJ, Bishop B, Townsend MJ, McKenzie AN, Lloyd CM. The

absence of interleukin 9 does not affect the development of allergen-in-

duced pulmonary inflammation nor airway hyperreactivity. J Exp Med

2002;195:51-7.

195. Temann UA, Ray P, Flavell RA. Pulmonary overexpression of IL-9

induces Th2 cytokine expression, leading to immune pathology. J Clin

Invest 2002;109:29-39.

196. Townsend JM, Fallon GP, Matthews JD, Smith P, Jolin EH, McKenzie

NA. IL-9-deficient mice establish fundamental roles for IL-9 in pulmo-

nary mastocytosis and goblet cell hyperplasia but not T cell develop-

ment. Immunity 2000;13:573-83.

197. Hershey GK. IL-13 receptors and signaling pathways: an evolving web.

J Allergy Clin Immunol 2003;111:677-90; quiz 91.

198. Seto Y, Nakajima H, Suto A, Shimoda K, Saito Y, Nakayama KI, et al.

Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient

mice. J Immunol 2003;170:1077-83.

199. Darnell JE Jr. Transcription factors as targets for cancer therapy. Nat

Rev Cancer 2002;2:740-9.

200. Yu H, Jove R. The STATs of cancer—new molecular targets come of

age. Nat Rev Cancer 2004;4:97-105.

201. Muthian G, Raikwar HP, Johnson C, Rajasingh J, Kalgutkar A, Marnett

LJ, et al. COX-2 inhibitors modulate IL-12 signaling through JAK-

STAT pathway leading to Th1 response in experimental allergic en-

cephalomyelitis. J Clin Immunol 2006;26:73-85.

202. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM,

et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a

Th2 bias and reverses paralysis in central nervous system autoimmune

disease. Nature 2002;420:78-84.

203. Arnaud C, Burger F, Steffens S, Veillard NR, Nguyen TH, Trono D,

et al. Statins reduce interleukin-6-induced C-reactive protein in human

hepatocytes: new evidence for direct antiinflammatory effects of statins.

Arterioscler Thromb Vasc Biol 2005;25:1231-6.

204. Gleason EL, Hogan JC, Stephens JM. Stabilization, not polymerization,

of microtubules inhibits the nuclear translocation of STATs in adipo-

cytes. Biochem Biophys Res Commun 2004;325:716-8.

Signal transducer and activator of transcription signals in allergic diseaseOverview of stat proteinsStructureSTAT PhosphorylationSTAT cofactorsSTAT nuclear import and exportSTAT trafficking determines cytokine sensitivity and responsesDephosphorylation and proteolytic processing of STATs

Stat functionsSTATs and regulatory T cellsSTATs and inflammationSTATs and apoptosis

Stat polymorphismsPharmaceutical targeting of jak-statConclusionReferences