stat6 transcription factor


Summary: A signal transducer and activator of transcription that mediates cellular responses to INTERLEUKIN-4. Stat6 has been shown to partner with NF-KAPPA B and CCAAT-ENHANCER-BINDING PROTEINS to regulate GENETIC TRANSCRIPTION of interleukin-4 responsive GENES.

Top Publications

  1. Choi H, Choi H, Han J, Jin S, Park J, Shin D, et al. IL-4 inhibits the melanogenesis of normal human melanocytes through the JAK2-STAT6 signaling pathway. J Invest Dermatol. 2013;133:528-36 pubmed publisher
  2. Perona Wright G, Mohrs K, Mayer K, Mohrs M. Differential regulation of IL-4Ralpha expression by antigen versus cytokine stimulation characterizes Th2 progression in vivo. J Immunol. 2010;184:615-23 pubmed publisher
    ..Together these data reveal a tightly controlled program of changing IL-4 responsiveness that characterizes the initiation, amplification, and restriction of a Th2 response in vivo. ..
  3. Knott M, Matthaei K, Foster P, Dent L. The roles of eotaxin and the STAT6 signalling pathway in eosinophil recruitment and host resistance to the nematodes Nippostrongylus brasiliensis and Heligmosomoides bakeri. Mol Immunol. 2009;46:2714-22 pubmed publisher
  4. Chen H, Reich N. Live cell imaging reveals continuous STAT6 nuclear trafficking. J Immunol. 2010;185:64-70 pubmed publisher
    The STAT6 transcription factor is essential for the development of protective immunity; however, the consequences of its activity can also contribute to the pathogenesis of autoimmune disease...
  5. Elo L, Jarvenpaa H, Tuomela S, Raghav S, Ahlfors H, Laurila K, et al. Genome-wide profiling of interleukin-4 and STAT6 transcription factor regulation of human Th2 cell programming. Immunity. 2010;32:852-62 pubmed publisher
    ..Because the STAT6 transcription factor is an upstream mediator required for interleukin-4 (IL-4)-induced Th2 cell differentiation, its targets ..
  6. Ong Y, Reese M, Boothroyd J. Toxoplasma rhoptry protein 16 (ROP16) subverts host function by direct tyrosine phosphorylation of STAT6. J Biol Chem. 2010;285:28731-40 pubmed publisher
    ..Furthermore, ROP16 co-immunoprecipitates with STAT6 from infected cells. Taken together, these data strongly suggest that STAT6 is a direct substrate for ROP16 in vivo. ..
  7. Younossi Z, Baranova A, Afendy A, Collantes R, Stepanova M, Manyam G, et al. Early gene expression profiles of patients with chronic hepatitis C treated with pegylated interferon-alfa and ribavirin. Hepatology. 2009;49:763-74 pubmed publisher
    ..Early gene expression during anti-HCV therapy may elucidate important molecular pathways that may be influencing the probability of achieving virologic response. ..
  8. El Kasmi K, Qualls J, Pesce J, Smith A, Thompson R, Henao Tamayo M, et al. Toll-like receptor-induced arginase 1 in macrophages thwarts effective immunity against intracellular pathogens. Nat Immunol. 2008;9:1399-406 pubmed publisher
    ..Specific elimination of Arg1 in macrophages favored host survival during T. gondii infection and decreased lung bacterial load during tuberculosis infection. ..
  9. Goenka S, Kaplan M. Transcriptional regulation by STAT6. Immunol Res. 2011;50:87-96 pubmed publisher
    ..In this review, we will describe our current understanding of the biological functions of STAT6 and summarize recent advances in understanding the molecular mechanisms by which STAT6 regulates transcription. ..

More Information


  1. Lesterhuis W, Punt C, Hato S, Eleveld Trancikova D, Jansen B, Nierkens S, et al. Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest. 2011;121:3100-8 pubmed publisher
    ..This dual action of platinum compounds may extend their therapeutic application in cancer patients and provides a rationale for their use in combination with immunostimulatory compounds. ..
  2. Wang Q, Bai X, Xu D, Li H, Xu C, Fang J. Association of polymorphisms of STAT6 and SO(2) with Chinese childhood asthma: a case-control study. Biomed Environ Sci. 2011;24:670-7 pubmed publisher
    ..05). Chinese children differed in polymorphisms of STAT6 and in its relation with childhood asthma. ..
  3. Tachdjian R, Mathias C, Al Khatib S, Bryce P, Kim H, Blaeser F, et al. Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. J Exp Med. 2009;206:2191-204 pubmed publisher
    ..Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4R alpha-dependent signaling. ..
  4. Kim E, Shin H, Lee C, Park H, Kim Y, Park H, et al. DNA methylation and not allelic variation regulates STAT6 expression in human T cells. Clin Exp Med. 2010;10:143-52 pubmed publisher
    b>STAT6 transcription factor, which has been implicated in commitment to Th2, is known to be activated by IL-4 and IL-13. Accordingly, STAT6 is primarily responsible for the transcriptional effects of IL-4 and IL-13...
  5. Scheinman E, Avni O. Transcriptional regulation of GATA3 in T helper cells by the integrated activities of transcription factors downstream of the interleukin-4 receptor and T cell receptor. J Biol Chem. 2009;284:3037-48 pubmed publisher
    ..Our findings suggest that different combinations of transcription factors downstream of the IL-4 receptor (IL-4R) and TCR finely modulate Gata3 gene expression from its two promoters for optimal Th2 differentiation. ..
  6. Szanto A, Balint B, Nagy Z, Barta E, Dezso B, Pap A, et al. STAT6 transcription factor is a facilitator of the nuclear receptor PPAR?-regulated gene expression in macrophages and dendritic cells. Immunity. 2010;33:699-712 pubmed publisher
    ..This interaction, underpinning cell type-specific responses, represents a unique way of controlling nuclear receptor signaling by inflammatory molecules in immune cells. ..
  7. Maier E, Hebenstreit D, Posselt G, Hammerl P, Duschl A, Horejs Hoeck J. Inhibition of suppressive T cell factor 1 (TCF-1) isoforms in naive CD4+ T cells is mediated by IL-4/STAT6 signaling. J Biol Chem. 2011;286:919-28 pubmed publisher
    ..Thus, this study provides a model for an IL-4/STAT6-dependent fine tuning mechanism of TCF-1-driven T helper cell polarization. ..
  8. Chapoval S, Dasgupta P, Dorsey N, Keegan A. Regulation of the T helper cell type 2 (Th2)/T regulatory cell (Treg) balance by IL-4 and STAT6. J Leukoc Biol. 2010;87:1011-8 pubmed publisher
    ..In this perspective, we discuss the regulation of Th2 cells by Tregs and vice versa, focusing on the interplay between the IL-4-activated STAT6/GATA3 pathway and Foxp3. ..
  9. Mandal D, Fu P, Levine A. REDOX regulation of IL-13 signaling in intestinal epithelial cells: usage of alternate pathways mediates distinct gene expression patterns. Cell Signal. 2010;22:1485-94 pubmed publisher
  10. Darcan Nicolaisen Y, Meinicke H, Fels G, Hegend O, Haberland A, Kühl A, et al. Small interfering RNA against transcription factor STAT6 inhibits allergic airway inflammation and hyperreactivity in mice. J Immunol. 2009;182:7501-8 pubmed publisher
    ..It may thus be considered as putative approach for treatment of allergic airway diseases such as asthma. ..
  11. Miyamoto H, Katsuyama E, Miyauchi Y, Hoshi H, Miyamoto K, Sato Y, et al. An essential role for STAT6-STAT1 protein signaling in promoting macrophage cell-cell fusion. J Biol Chem. 2012;287:32479-84 pubmed
    ..We conclude that the STAT6-STAT1 axis regulates OC-STAMP and DC-STAMP expression and governs fusogenic mechanisms in FBGCs. ..
  12. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol. 2011;11:750-61 pubmed publisher
    ..In this Review, we summarize the current knowledge of transcriptional and chromatin-mediated control of macrophage polarization in physiology and disease. ..
  13. Schweizer L, Koelsche C, Sahm F, Piro R, Capper D, Reuss D, et al. Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein. Acta Neuropathol. 2013;125:651-8 pubmed publisher
    ..This immunohistochemical assay may prove valuable for the differentiation of HPC and SFT from other mesenchymal neoplasms...
  14. Velavan T, Bechlars S, Tomiuk J, Kremsner P, Kun J. Molecular characterization of regulatory polymorphisms in the promoter region of the STAT6 gene in a Gabonese population. Mem Inst Oswaldo Cruz. 2011;106:65-9 pubmed
    ..One promoter variant, rs3024944 (G/C), revealed an altered expression of the marker gene. The identification of function-altering SNPs in the promoter may facilitate studying parasite susceptibility in association studies...
  15. Ricardo Gonzalez R, Red Eagle A, Odegaard J, Jouihan H, Morel C, Heredia J, et al. IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proc Natl Acad Sci U S A. 2010;107:22617-22 pubmed publisher
  16. Stritesky G, Muthukrishnan R, Sehra S, Goswami R, Pham D, Travers J, et al. The transcription factor STAT3 is required for T helper 2 cell development. Immunity. 2011;34:39-49 pubmed publisher
    ..Thus, STAT3 cooperates with STAT6 in promoting Th2 cell development. These results demonstrate that differentiating T helper cells integrate multiple STAT protein signals during Th2 cell development. ..
  17. Mandal P, Pratt B, Barnes M, McMullen M, Nagy L. Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin. J Biol Chem. 2011;286:13460-9 pubmed publisher
  18. Hirota J, Ask K, Fritz D, Ellis R, Wattie J, Richards C, et al. Role of STAT6 and SMAD2 in a model of chronic allergen exposure: a mouse strain comparison study. Clin Exp Allergy. 2009;39:147-58 pubmed publisher
    ..Activation of signalling pathways downstream from IL-13 and TGF-beta1 may be more relevant in disease progression than elevations in airway inflammation alone. ..
  19. Oh S, Zheng T, Kim Y, Cohn L, Homer R, McKenzie A, et al. A critical role of SHP-1 in regulation of type 2 inflammation in the lung. Am J Respir Cell Mol Biol. 2009;40:568-74 pubmed publisher
    ..These findings suggest that SHP-1 plays a critical role in regulating the IL-4/IL-13 signaling pathway and in maintaining lung homeostasis. ..
  20. Robinson D, Wu Y, Kalyana Sundaram S, Cao X, Lonigro R, Sung Y, et al. Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. Nat Genet. 2013;45:180-5 pubmed publisher
    ..These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. ..
  21. Tachdjian R, Al Khatib S, Schwinglshackl A, Kim H, Chen A, Blasioli J, et al. In vivo regulation of the allergic response by the IL-4 receptor alpha chain immunoreceptor tyrosine-based inhibitory motif. J Allergy Clin Immunol. 2010;125:1128-1136.e8 pubmed publisher
    ..These results point to a physiologic negative regulatory role for the Y709 ITIM in signaling through IL-4Ralpha, especially by IL-13. ..
  22. Baus D, Nonnenmacher F, Jankowski S, Doring C, Brautigam C, Frank M, et al. STAT6 and STAT1 are essential antagonistic regulators of cell survival in classical Hodgkin lymphoma cell line. Leukemia. 2009;23:1885-93 pubmed publisher
    ..Forced expression of STAT1 was able to induce apoptosis in cHL cell line L1236. These findings indicate that both STAT6 and STAT1 can act as important antagonistic regulators in the pathogenesis of cHL. ..
  23. Liu C, Schain F, Han H, Xu D, Andersson Sand H, Forsell P, et al. Epigenetic and transcriptional control of the 15-lipoxygenase-1 gene in a Hodgkin lymphoma cell line. Exp Cell Res. 2012;318:169-76 pubmed publisher
    ..These prerequisites are fulfilled in the L1236 cell line, but not in the L428 cell line. ..
  24. Walker W, Healey G, Hopkin J. RNA interference of STAT6 rapidly attenuates ongoing interleukin-13-mediated events in lung epithelial cells. Immunology. 2009;127:256-66 pubmed publisher
  25. Chiba Y, Todoroki M, Nishida Y, Tanabe M, Misawa M. A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice. Am J Respir Cell Mol Biol. 2009;41:516-24 pubmed publisher
    ..These findings suggest that the inhibitory effects of STAT6 inhibitory agents, such as AS1517499, both on RhoA and IL-13 up-regulations might be useful for asthma treatment. ..
  26. Qualls J, Neale G, Smith A, Koo M, DeFreitas A, Zhang H, et al. Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling. Sci Signal. 2010;3:ra62 pubmed publisher
  27. Merk B, Owens J, Lopes M, Silva C, Hussaini I. STAT6 expression in glioblastoma promotes invasive growth. BMC Cancer. 2011;11:184 pubmed publisher
    ..This report thus identifies STAT6 as a new and potentially promising therapeutic target. ..
  28. Kim Y, Kwon E, Jeon J, So I, Kim I, Choi M, et al. Activation of the STAT6 transcription factor in Jurkat T-cells by the herpesvirus saimiri Tip protein. J Gen Virol. 2012;93:330-40 pubmed publisher
    ..In this study, we found that Tip interacts with the STAT6 transcription factor and induces phosphorylation of STAT6 in T-cells...
  29. Mishra B, Gundra U, Teale J. STAT6?/? mice exhibit decreased cells with alternatively activated macrophage phenotypes and enhanced disease severity in murine neurocysticercosis. J Neuroimmunol. 2011;232:26-34 pubmed publisher
  30. Chen H, Sun H, You F, Sun W, Zhou X, Chen L, et al. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell. 2011;147:436-46 pubmed publisher
    ..Thus, STAT6 mediates immune signaling in response to both cytokines at the plasma membrane, and virus infection at the endoplasmic reticulum...
  31. Granada M, Wilk J, Tuzova M, Strachan D, Weidinger S, Albrecht E, et al. A genome-wide association study of plasma total IgE concentrations in the Framingham Heart Study. J Allergy Clin Immunol. 2012;129:840-845.e21 pubmed publisher
    ..It also confirmed the association of the known susceptibility loci FCER1A, STAT6, and IL13 for the dysregulation of total IgE. ..
  32. Zhang S, Bernard D, Khan W, Kaplan M, Bramson J, Wan Y. CD4+ T-cell-mediated anti-tumor immunity can be uncoupled from autoimmunity via the STAT4/STAT6 signaling axis. Eur J Immunol. 2009;39:1252-9 pubmed publisher
    ..Our results offer a possibility to elicit specific anti-tumor responses without triggering unwanted tissue autoimmune diseases...
  33. Turner J, Jones C. Regulation of mucin expression in respiratory diseases. Biochem Soc Trans. 2009;37:877-81 pubmed publisher
    ..An understanding of the origin and processes regulating goblet cell formation in human airway epithelial cells has important implications for the identification of therapeutic targets to treat respiratory diseases. ..
  34. Chmielecki J, Crago A, Rosenberg M, O Connor R, Walker S, Ambrogio L, et al. Whole-exome sequencing identifies a recurrent NAB2-STAT6 fusion in solitary fibrous tumors. Nat Genet. 2013;45:131-2 pubmed publisher
  35. Ahn H, Kim J, Ryu K, Nam H. STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage. Parasitol Res. 2009;105:1445-53 pubmed publisher
    ..This suggests that T. gondii exploits cytokine cross-regulation through STAT6 activation to obviate various toxoplasmacidal reactions by interferon-gamma. ..
  36. Junttila I, Mizukami K, Dickensheets H, Meier Schellersheim M, Yamane H, Donnelly R, et al. Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac regulates relative cytokine sensitivity. J Exp Med. 2008;205:2595-608 pubmed publisher
    ..These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine. ..
  37. Heller N, Qi X, Junttila I, Shirey K, Vogel S, Paul W, et al. Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages. Sci Signal. 2008;1:ra17 pubmed publisher
    ..Thus, IL-4 activates signaling pathways through type I IL-4Rs qualitatively differently from IL-13, which cooperate to induce optimal gene expression. ..
  38. Ranasinghe C, Ramshaw I. Immunisation route-dependent expression of IL-4/IL-13 can modulate HIV-specific CD8(+) CTL avidity. Eur J Immunol. 2009;39:1819-30 pubmed publisher
    ..STAT6(-/-) mice also showed memory CTL of higher avidity. Furthermore, CCL5 expression in K(d)Gag(197-205)-specific CTL was also regulated by IL-4/IL-13. ..
  39. Tamachi T, Takatori H, Fujiwara M, Hirose K, Maezawa Y, Kagami S, et al. STAT6 inhibits T-bet-independent Th1 cell differentiation. Biochem Biophys Res Commun. 2009;382:751-5 pubmed publisher
    ..These results indicate that STAT6 inhibits T-bet-independent Th1 cell differentiation by suppressing IL-12-STAT4 signaling. ..
  40. Chapoval S, Dasgupta P, Smith E, DeTolla L, Lipsky M, Kelly Welch A, et al. STAT6 expression in multiple cell types mediates the cooperative development of allergic airway disease. J Immunol. 2011;186:2571-83 pubmed publisher
    ..Taken together, our studies demonstrate multiple STAT6-dependent and -independent features of allergic inflammation, which may impact treatments targeting STAT6...
  41. Ueta M, Mizushima K, Yokoi N, Naito Y, Kinoshita S. Expression of the interleukin-4 receptor alpha in human conjunctival epithelial cells. Br J Ophthalmol. 2010;94:1239-43 pubmed publisher
    ..HCjECs expressed functioning IL-4Ralpha, and IL-4 stimulation induced the expression of several genes. ..
  42. Li B, Xu S, Li F, Zou X, Saimaiti A, Simayi D, et al. Stat6 activity-related Th2 cytokine profile and tumor growth advantage of human colorectal cancer cells in vitro and in vivo. Cell Signal. 2012;24:718-25 pubmed publisher
    ..These findings may imply why Stat6 pathway is constitutively activated in a number of human malignancies. ..
  43. Yu H, Liu P, Lin Y, Chen W, Lee J, Wang L, et al. Interleukin 4 and STAT6 gene polymorphisms are associated with systemic lupus erythematosus in Chinese patients. Lupus. 2010;19:1219-28 pubmed publisher
    ..59 + 3.53 versus 5.67 + 11.28 pg/ml, p = 0.042). These results indicated that IL4 and STAT6 genes might be involved in the etiology of SLE and potentially increased SLE risk through their interaction effect in Chinese patients. ..
  44. Wei L, Vahedi G, Sun H, Watford W, Takatori H, Ramos H, et al. Discrete roles of STAT4 and STAT6 transcription factors in tuning epigenetic modifications and transcription during T helper cell differentiation. Immunity. 2010;32:840-51 pubmed publisher
    ..Clusters of genes negatively regulated by STATs were also identified, highlighting previously unappreciated repressive roles of STATs. Therefore, STAT4 and STAT6 play wide regulatory roles in T helper cell specification. ..
  45. Speiran K, Bailey D, Fernando J, Macey M, Barnstein B, Kolawole M, et al. Endogenous suppression of mast cell development and survival by IL-4 and IL-10. J Leukoc Biol. 2009;85:826-36 pubmed publisher
    ..Loss of this homeostasis, perhaps via genetic polymorphism, could contribute to the etiology of mast cell-associated disease. ..
  46. Iff J, Wang W, Sajic T, Oudry N, Gueneau E, Hopfgartner G, et al. Differential proteomic analysis of STAT6 knockout mice reveals new regulatory function in liver lipid homeostasis. J Proteome Res. 2009;8:4511-24 pubmed publisher
    ..In conclusion, our study revealed a so far uncharacterized role for STAT6 in regulating liver lipid homeostasis and demonstrates the importance of anti-inflammatory signaling in the defense against the development of liver steatosis. ..
  47. Maier E, Wirnsberger G, Horejs Hoeck J, Duschl A, Hebenstreit D. Identification of a distal tandem STAT6 element within the CCL17 locus. Hum Immunol. 2007;68:986-92 pubmed publisher
    ..Collectively these data reveal an additional element involved in the regulation of CCL17 expression. ..
  48. Moynihan B, Tolloczko B, Michoud M, Tamaoka M, Ferraro P, Martin J. MAP kinases mediate interleukin-13 effects on calcium signaling in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2008;295:L171-7 pubmed publisher
    ..We conclude that IL-13 induces potentiation of Ca(2+) responses to contractile agonists by affecting mechanisms downstream of receptors. JNK and ERK MAPKs modulate these mechanisms. ..
  49. So E, Oh J, Jang J, Kim J, Lee C. Ras/Erk pathway positively regulates Jak1/STAT6 activity and IL-4 gene expression in Jurkat T cells. Mol Immunol. 2007;44:3416-26 pubmed
    ..Together, the results indicate that there is a functional cross-talk between Ras/Erk and IL-4/Jak1/STAT6, which contributes to the regulation of IL-4 transcription in T cells. ..
  50. Zeng Y, Zhang X, Huang Z, Cheng L, Yao S, Qin D, et al. Intracellular Tat of human immunodeficiency virus type 1 activates lytic cycle replication of Kaposi's sarcoma-associated herpesvirus: role of JAK/STAT signaling. J Virol. 2007;81:2401-17 pubmed
    ..These findings suggest that Tat may participate in KS pathogenesis by inducing KSHV replication and increasing KSHV viral load. These data also suggest that JAK/STAT signaling may be of therapeutic value in AIDS-related KS patients. ..
  51. Bonaparte K, Hudson C, Wu C, Massa P. Inverse regulation of inducible nitric oxide synthase (iNOS) and arginase I by the protein tyrosine phosphatase SHP-1 in CNS glia. Glia. 2006;53:827-35 pubmed
    ..Thus, we propose that SHP-1 is a critical regulator of innate immunity to virus infections in CNS cells. ..
  52. van Panhuys N, Tang S, Prout M, Camberis M, Scarlett D, Roberts J, et al. In vivo studies fail to reveal a role for IL-4 or STAT6 signaling in Th2 lymphocyte differentiation. Proc Natl Acad Sci U S A. 2008;105:12423-8 pubmed publisher
  53. Kabesch M, Schedel M, Carr D, Woitsch B, Fritzsch C, Weiland S, et al. IL-4/IL-13 pathway genetics strongly influence serum IgE levels and childhood asthma. J Allergy Clin Immunol. 2006;117:269-74 pubmed
    ..054). These data indicate that only the combined analyses of genetic alterations in the IL-4/IL-13 pathway reveal its actual significance to the development of atopy and childhood asthma. ..