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Gene Review

Stat6  -  signal transducer and activator of...

Mus musculus

Synonyms: Signal transducer and transcription activator 6
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Disease relevance of Stat6


High impact information on Stat6


Chemical compound and disease context of Stat6


Biological context of Stat6

  • Here, we explored the role of Stat4 and Stat6 in innate immunity during septic peritonitis [1].
  • This region of the receptor is not required for cell growth, demonstrating that Stat6 tyrosine phosphorylation does not contribute to mitogenesis [11].
  • The sequence of the human cDNA was identical to the recently published sequence for interleukin-4 (IL-4)-Stat (J. Hou, U. Schindler, W.J. Henzel, T.C. Ho, M. Brasseur, and S. L. McKnight, Science 265:1701-1706, 1994), while the murine Stat6 amino acid and nucleotide sequences were 83 and 84% identical to the human sequences, respectively [11].
  • Unlike in wild-type mice, treatment of Stat6 knockout recipients with Ad-IL-13 failed to improve hepatic function/histology [2].
  • Gingival Il1b gene expression increased further and Stat6 gene expression was turned on after P. gingivalis infection in BALB/cByJ mice but not in A/J mice [12].

Anatomical context of Stat6

  • In this report, we demonstrate that progenitor cell numbers and cycling status in vivo are dramatically increased in mice deficient in Stat6 and decreased in mice deficient in Stat4, targeted mutations which also alter T helper cell polarization [13].
  • We investigated the cellular location of phosphorylated Stat6 and Stat6 DNA binding activity in A201.1 murine B cells and primary splenocytes [14].
  • Stat6-dependent gene transcription promotes expulsion of N. brasiliensis solely through effects on non-bone marrow-derived cells that may include enhancement of intestinal smooth muscle contractility, changes in intestinal epithelial cell function, and increased intestinal mucus secretion [15].
  • Unexpectedly, IL-4's enhancement of PDGF-induced [3H]thymidine incorporation was greatly diminished in Stat6-/-, but not wild-type fibroblasts [16].
  • Compared to wild-type (WT) mice, schistosome granulomas in Stat6 knockout (KO) mice lacked eosinophils and had Th1 features [3].

Associations of Stat6 with chemical compounds

  • Strikingly, Stat6-deficient mice failed to develop airway hyperresponsiveness (AHR), which was observed in their wild-type littermates after allergen provocation [17].
  • Cells treated with an inhibitor of nuclear export, leptomycin B, were unable to maintain Stat6 activation [18].
  • IL-13, H. polygyrus, and N. brasiliensis, but not IL-4, also increased contractility to acetylcholine by mechanisms that involved Stat6 and enteric nerves [19].
  • Here we constructed Stat6:ER, a Stat6-estrogen receptor fusion protein that can be activated by 4-hydroxy-tamoxifen, independently of IL-4 and endogenous Stat6 [20].
  • Variants of IL-4Ralpha encoding isoleucine instead of valine at position 50 (I50 vs V50, respectively) can signal increased Stat6-dependent transcriptional activity, whether in an I50, Q551 or I50, R551 haplotype [21].

Physical interactions of Stat6

  • Detergent treatment restored Stat6 DNA binding activity in cytoplasmic extracts of IL-4-stimulated cells [14].
  • We also prepared transgenes that were truncated at -150 (rather than -2100) and therefore included the wild-type Stat6 binding site at -123 and the three wild-type NF-kappaB sites [22].
  • Previous studies have demonstrated that BCL-6 and Stat6 can both bind and regulate the Iepsilon promoter that controls immunoglobulin heavy chain class switching to IgE [23].

Enzymatic interactions of Stat6


Regulatory relationships of Stat6

  • In contrast, Stat6 signaling promotes immunity to T. spiralis both through effects on bone marrow-derived cells that can be reproduced by treating mice with IL-4 or IL-13 and through effects on non-bone marrow-derived cells [15].
  • Moreover, a reporter assay showed that a constitutively active form of Stat5a but not Stat6 activated the SOCS3 promoter [25].
  • Using a novel cell surface affinity matrix technique, we found that IL-4-secreting Stat6-deficient T cells stably expressed GATA-3 and Th2 phenotype [26].
  • Increased susceptibility of Stat4-deficient and enhanced resistance in Stat6-deficient mice to infection with Trypanosoma cruzi [27].
  • Studies in mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis demonstrated that IL-4/IL-13 activation of Stat6 suppresses development of intestinal mastocytosis and does not contribute to IL-4/IL-13 production, but is still essential for parasite expulsion [28].
  • CD8+ T cells expressing a constitutively active mutant form Stat6 (Stat6VT) failed to express VLA-4 even in the absence of IL-4-stimulation [29].

Other interactions of Stat6

  • Strong expression of Stat3, Stat5a, and Stat6 was observed in the RPE [30].
  • In contrast to progressive growth of P1.HTR tumors in wild-type mice, and aggressive growth even of IL-12-transfected P1.HTR in Stat1(-/-) mice, P1.HTR was spontaneously rejected by Stat6(-/-) mice [31].
  • At the mechanistic level, bacterial levels in Stat6-/- mice were much lower than in WT mice, which was associated with increased peritoneal levels of interleukin (IL)-12, tumor necrosis factor (TNF)-alpha, macrophage-derived chemokine (MDC), and C10, known to enhance bacterial clearance [1].
  • Helminth regulation of host IL-4Ralpha/Stat6 signaling: mechanism underlying NOS-2 inhibition by Trichinella spiralis [32].
  • Confocal microscopy confirmed the presence of phosphorylated Stat6 in the cytoplasm of IL-4-treated cells [14].

Analytical, diagnostic and therapeutic context of Stat6

  • Signal transducer and activator of transcription (Stat)4 and Stat6 are transcription factors that provide type 1 and type 2 response, respectively [1].
  • Using a partial 90-min lobar warm ischemia model, groups of wild-type and Stat6-deficient knockout mice were assessed for the severity of hepatocellular damage at 6 hr postreperfusion [2].
  • To investigate the functional role of Stat6 in IL-4 signalling, we generated mice deficient in Stat6 by gene targeting [5].
  • Electrophoretic mobility shift assays demonstrate that BCL-6 can bind, with different affinities, to several DNA elements recognized by Stat6 [33].
  • In the present study, novel IL-4- and Stat6-regulated genes were discovered by using Stat6(-/-) mice and Affymetrix oligonucleotide arrays [34].


  1. Pivotal role of signal transducer and activator of transcription (Stat)4 and Stat6 in the innate immune response during sepsis. Matsukawa, A., Kaplan, M.H., Hogaboam, C.M., Lukacs, N.W., Kunkel, S.L. J. Exp. Med. (2001) [Pubmed]
  2. Interleukin 13 gene transfer in liver ischemia and reperfusion injury: role of Stat6 and TLR4 pathways in cytoprotection. Ke, B., Shen, X.D., Gao, F., Busuttil, R.W., Kupiec-Weglinski, J.W. Hum. Gene Ther. (2004) [Pubmed]
  3. Interleukin-4 receptor alpha chain and STAT6 signaling inhibit gamma interferon but not Th2 cytokine expression within schistosome granulomas. Metwali, A., Blum, A., Elliott, D.E., Weinstock, J.V. Infect. Immun. (2002) [Pubmed]
  4. Differential requirement of signal transducer and activator of transcription-4 (Stat4) and Stat6 in a thyrotropin receptor-289-adenovirus-induced model of Graves' hyperthyroidism. Land, K.J., Gudapati, P., Kaplan, M.H., Seetharamaiah, G.S. Endocrinology (2006) [Pubmed]
  5. Essential role of Stat6 in IL-4 signalling. Takeda, K., Tanaka, T., Shi, W., Matsumoto, M., Minami, M., Kashiwamura, S., Nakanishi, K., Yoshida, N., Kishimoto, T., Akira, S. Nature (1996) [Pubmed]
  6. Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Shimoda, K., van Deursen, J., Sangster, M.Y., Sarawar, S.R., Carson, R.T., Tripp, R.A., Chu, C., Quelle, F.W., Nosaka, T., Vignali, D.A., Doherty, P.C., Grosveld, G., Paul, W.E., Ihle, J.N. Nature (1996) [Pubmed]
  7. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. Kaplan, M.H., Whitfield, J.R., Boros, D.L., Grusby, M.J. J. Immunol. (1998) [Pubmed]
  8. Effect of targeted disruption of signal transducer and activator of transcription (Stat)4 and Stat6 genes on the autoimmune diabetes development induced by multiple low doses of streptozotocin. Cetkovic-Cvrlje, M., Uckun, F.M. Clin. Immunol. (2005) [Pubmed]
  9. Stat6-deficient mice develop airway hyperresponsiveness and peribronchial fibrosis during chronic fungal asthma. Blease, K., Schuh, J.M., Jakubzick, C., Lukacs, N.W., Kunkel, S.L., Joshi, B.H., Puri, R.K., Kaplan, M.H., Hogaboam, C.M. Am. J. Pathol. (2002) [Pubmed]
  10. Abrogation of lung inflammation in sensitized Stat6-deficient mice is dependent on the allergen inhalation procedure. Trifilieff, A., El-Hasim, A., Corteling, R., Owen, C.E. Br. J. Pharmacol. (2000) [Pubmed]
  11. Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Quelle, F.W., Shimoda, K., Thierfelder, W., Fischer, C., Kim, A., Ruben, S.M., Cleveland, J.L., Pierce, J.H., Keegan, A.D., Nelms, K. Mol. Cell. Biol. (1995) [Pubmed]
  12. Quantitative gene expression profiling implicates genes for susceptibility and resistance to alveolar bone loss. Hart, G.T., Shaffer, D.J., Akilesh, S., Brown, A.C., Moran, L., Roopenian, D.C., Baker, P.J. Infect. Immun. (2004) [Pubmed]
  13. Th1 cells regulate hematopoietic progenitor cell homeostasis by production of oncostatin M. Broxmeyer, H.E., Bruns, H.A., Zhang, S., Cooper, S., Hangoc, G., McKenzie, A.N., Dent, A.L., Schindler, U., Naeger, L.K., Hoey, T., Kaplan, M.H. Immunity (2002) [Pubmed]
  14. DNA binding activity of cytoplasmic phosphorylated Stat6 is masked by an interaction with a detergent-sensitive factor. Daines, M.O., Andrews, R.P., Chen, W., El-Zayaty, S.A., Hershey, G.K. J. Biol. Chem. (2003) [Pubmed]
  15. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Finkelman, F.D., Shea-Donohue, T., Morris, S.C., Gildea, L., Strait, R., Madden, K.B., Schopf, L., Urban, J.F. Immunol. Rev. (2004) [Pubmed]
  16. Consequences of Stat6 deletion on Sis/PDGF- and IL-4-induced proliferation and transcriptional activation in murine fibroblasts. Kriebel, P., Patel, B.K., Nelson, S.A., Grusby, M.J., LaRochelle, W.J. Oncogene (1999) [Pubmed]
  17. Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. Kuperman, D., Schofield, B., Wills-Karp, M., Grusby, M.J. J. Exp. Med. (1998) [Pubmed]
  18. Analysis of the life cycle of stat6. Continuous cycling of STAT6 is required for IL-4 signaling. Andrews, R.P., Ericksen, M.B., Cunningham, C.M., Daines, M.O., Hershey, G.K. J. Biol. Chem. (2002) [Pubmed]
  19. Dependence of IL-4, IL-13, and nematode-induced alterations in murine small intestinal smooth muscle contractility on Stat6 and enteric nerves. Zhao, A., McDermott, J., Urban, J.F., Gause, W., Madden, K.B., Yeung, K.A., Morris, S.C., Finkelman, F.D., Shea-Donohue, T. J. Immunol. (2003) [Pubmed]
  20. Ectopic expression of activated Stat6 induces the expression of Th2-specific cytokines and transcription factors in developing Th1 cells. Kurata, H., Lee, H.J., O'Garra, A., Arai, N. Immunity (1999) [Pubmed]
  21. An IL-4R alpha allelic variant, I50, acts as a gain-of-function variant relative to V50 for Stat6, but not Th2 differentiation. Stephenson, L., Johns, M.H., Woodward, E., Mora, A.L., Boothby, M. J. Immunol. (2004) [Pubmed]
  22. NF-kappaB elements associated with the Stat6 site in the germline gamma1 immunoglobulin promoter are not necessary for the transcriptional response to CD40 ligand. Berton, M.T., Linehan, L.A., Wick, K.R., Dunnick, W.A. Int. Immunol. (2004) [Pubmed]
  23. Repression of an interleukin-4-responsive promoter requires cooperative BCL-6 function. Harris, M.B., Mostecki, J., Rothman, P.B. J. Biol. Chem. (2005) [Pubmed]
  24. Stat5a regulates T helper cell differentiation by several distinct mechanisms. Kagami , S., Nakajima, H., Suto, A., Hirose, K., Suzuki, K., Morita, S., Kato, I., Saito, Y., Kitamura, T., Iwamoto, I. Blood (2001) [Pubmed]
  25. Stat5a inhibits IL-12-induced Th1 cell differentiation through the induction of suppressor of cytokine signaling 3 expression. Takatori, H., Nakajima, H., Kagami, S., Hirose, K., Suto, A., Suzuki, K., Kubo, M., Yoshimura, A., Saito, Y., Iwamoto, I. J. Immunol. (2005) [Pubmed]
  26. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Ouyang, W., Löhning, M., Gao, Z., Assenmacher, M., Ranganath, S., Radbruch, A., Murphy, K.M. Immunity (2000) [Pubmed]
  27. Increased susceptibility of Stat4-deficient and enhanced resistance in Stat6-deficient mice to infection with Trypanosoma cruzi. Tarleton, R.L., Grusby, M.J., Zhang, L. J. Immunol. (2000) [Pubmed]
  28. Stat6 signaling promotes protective immunity against Trichinella spiralis through a mast cell- and T cell-dependent mechanism. Urban, J.F., Schopf, L., Morris, S.C., Orekhova, T., Madden, K.B., Betts, C.J., Gamble, H.R., Byrd, C., Donaldson, D., Else, K., Finkelman, F.D. J. Immunol. (2000) [Pubmed]
  29. Stat6 signaling suppresses VLA-4 expression by CD8+ T cells and limits their ability to infiltrate tumor lesions in vivo. Sasaki, K., Zhao, X., Pardee, A.D., Ueda, R., Fujita, M., Sehra, S., Kaplan, M.H., Kane, L.P., Okada, H., Storkus, W.J. J. Immunol. (2008) [Pubmed]
  30. Expression and activation of STAT proteins during mouse retina development. Zhang, S.S., Wei, J.Y., Li, C., Barnstable, C.J., Fu, X.Y. Exp. Eye Res. (2003) [Pubmed]
  31. Cutting edge: spontaneous rejection of poorly immunogenic P1.HTR tumors by Stat6-deficient mice. Kacha, A.K., Fallarino, F., Markiewicz, M.A., Gajewski, T.F. J. Immunol. (2000) [Pubmed]
  32. Helminth regulation of host IL-4Ralpha/Stat6 signaling: mechanism underlying NOS-2 inhibition by Trichinella spiralis. Bian, K., Zhong, M., Harari, Y., Lai, M., Weisbrodt, N., Murad, F. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  33. Transcriptional repression of Stat6-dependent interleukin-4-induced genes by BCL-6: specific regulation of iepsilon transcription and immunoglobulin E switching. Harris, M.B., Chang, C.C., Berton, M.T., Danial, N.N., Zhang, J., Kuehner, D., Ye, B.H., Kvatyuk, M., Pandolfi, P.P., Cattoretti, G., Dalla-Favera, R., Rothman, P.B. Mol. Cell. Biol. (1999) [Pubmed]
  34. Identification of novel IL-4/Stat6-regulated genes in T lymphocytes. Chen, Z., Lund, R., Aittokallio, T., Kosonen, M., Nevalainen, O., Lahesmaa, R. J. Immunol. (2003) [Pubmed]
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