Gene Symbol: Stat4
Description: signal transducer and activator of transcription 4
Alias: signal transducer and activator of transcription 4
Species: mouse
Products:     Stat4

Top Publications

  1. Darnell J. STATs and gene regulation. Science. 1997;277:1630-5 pubmed
    ..The discovery of a STAT in Drosophila, and most recently in Dictyostelium discoideum, implies an ancient evolutionary origin for this dual-function set of proteins. ..
  2. Good S, Thieu V, Mathur A, Yu Q, Stritesky G, Yeh N, et al. Temporal induction pattern of STAT4 target genes defines potential for Th1 lineage-specific programming. J Immunol. 2009;183:3839-47 pubmed publisher
    b>STAT4 is a critical component in the development of inflammatory adaptive immune responses. It has been extensively characterized as a lineage-determining factor in Th1 development...
  3. Nguyen K, Salazar Mather T, Dalod M, Van Deusen J, Wei X, Liew F, et al. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol. 2002;169:4279-87 pubmed
    ..IL-12/STAT4 was critical for NK cell IFN-gamma expression, whereas IFN-alphabeta/STAT1 were required for induction of ..
  4. Tarleton R, Grusby M, Zhang L. Increased susceptibility of Stat4-deficient and enhanced resistance in Stat6-deficient mice to infection with Trypanosoma cruzi. J Immunol. 2000;165:1520-5 pubmed
    ..cruzi, mice with induced deficiencies in the Stat4 or Stat6 genes were infected with T. cruzi...
  5. Villarino A, Stumhofer J, Saris C, Kastelein R, De Sauvage F, Hunter C. IL-27 limits IL-2 production during Th1 differentiation. J Immunol. 2006;176:237-47 pubmed
  6. Lee S, Fragoso M, Biron C. Cutting edge: a novel mechanism bridging innate and adaptive immunity: IL-12 induction of CD25 to form high-affinity IL-2 receptors on NK cells. J Immunol. 2012;189:2712-6 pubmed publisher
    ..The cytokines act ex vivo to increase CD25 levels, and IL-12, IL-12R, and STAT4, but not the NK activating receptor Ly49H, are required for peak induction in vivo...
  7. Miyagi T, Gil M, Wang X, Louten J, Chu W, Biron C. High basal STAT4 balanced by STAT1 induction to control type 1 interferon effects in natural killer cells. J Exp Med. 2007;204:2383-96 pubmed
    ..Regulation of their access to particular signaling pathways is poorly understood. STAT4 is important for IFN-gamma induction, and NK cells are major producers of this cytokine...
  8. Banerjee K, Biswas P, Rouse B. Role of Stat4-mediated signal transduction events in the generation of aggressor CD4+ T cells in herpetic stromal keratitis pathogenesis. J Interferon Cytokine Res. 2007;27:65-75 pubmed
    ..involved in the development of aggressor CD4(+) T cells, ocular HSV infection was followed in mice deficient in Stat4 (Stat4(-/-) mice), the signal transducer for the cytokine interleukin-12 (IL-12)...
  9. Hoey T, Zhang S, Schmidt N, Yu Q, Ramchandani S, Xu X, et al. Distinct requirements for the naturally occurring splice forms Stat4alpha and Stat4beta in IL-12 responses. EMBO J. 2003;22:4237-48 pubmed
    ..We have isolated an alternatively spliced isoform of Stat4, termed Stat4beta, which lacks 44 amino acids at the C-terminus, encompassing the putative transcriptional ..

More Information


  1. Liu K, Gaffen S, Goldsmith M. JAK/STAT signaling by cytokine receptors. Curr Opin Immunol. 1998;10:271-8 pubmed
    ..This signaling pathway influences normal cell survival and growth mechanisms and may contribute to oncogenic transformation. ..
  2. Nguyen K, Watford W, Salomon R, Hofmann S, Pien G, Morinobu A, et al. Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection. Science. 2002;297:2063-6 pubmed
    ..Here we show that IFN-alpha/beta activate STAT4 directly (STAT, signal transducers and activators of transcription) and that this is required for IFN-gamma ..
  3. Kim S, Gunst K, Sarvetnick N. STAT4/6-dependent differential regulation of chemokine receptors. Clin Immunol. 2006;118:250-7 pubmed
    ..Signal transducers and activators of transcription (STATs), in particular STAT4 and STAT6, are essential for the development of Th1 and Th2 cells, respectively...
  4. Usui T, Nishikomori R, Kitani A, Strober W. GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rbeta2 chain or T-bet. Immunity. 2003;18:415-28 pubmed
    To further understand the interaction among GATA-3, Stat4, and T-bet in helper T cell development, we first showed that retroviral expression of GATA-3 in developing Th1 cells suppresses Th1 development through downregulation of Stat4 ..
  5. O Malley J, Sehra S, Thieu V, Yu Q, Chang H, Stritesky G, et al. Signal transducer and activator of transcription 4 limits the development of adaptive regulatory T cells. Immunology. 2009;127:587-95 pubmed publisher
    ..b>Signal transducer and activator of transcription 4 (STAT4) is critical for the response to IL-12, although there is a parallel pathway ..
  6. Harrington L, Hatton R, Mangan P, Turner H, Murphy T, Murphy K, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005;6:1123-32 pubmed
    ..naive precursor cells to differentiate into T(H)-17 cells independently of the transcription factors STAT1, T-bet, STAT4 and STAT6...
  7. Agarwal S, Rao A. Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity. 1998;9:765-75 pubmed
    ..We propose that chromatin remodeling of cytokine gene loci is functionally associated with productive T cell differentiation and may explain the coordinate regulation of Th2 cytokine genes. ..
  8. Gil M, Ploquin M, Watford W, Lee S, Kim K, Wang X, et al. Regulating type 1 IFN effects in CD8 T cells during viral infections: changing STAT4 and STAT1 expression for function. Blood. 2012;120:3718-28 pubmed publisher
    ..conditionally activate all of the signal transducers and activators of transcription molecules (STATs), including STAT4. The best-characterized signaling pathways use STAT1, however, and type 1 IFN inhibition of cell proliferation is ..
  9. Syrbe U, Hoffmann U, Schlawe K, Liesenfeld O, Erb K, Hamann A. Microenvironment-dependent requirement of STAT4 for the induction of P-selectin ligands and effector cytokines on CD4+ T cells in healthy and parasite-infected mice. J Immunol. 2006;177:7673-9 pubmed
    ..b>STAT4 is strongly involved in these processes...
  10. Curtsinger J, Valenzuela J, Agarwal P, Lins D, Mescher M. Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol. 2005;174:4465-9 pubmed
    ..We show that IFN-alpha beta can provide the third signal directly to CD8 T cells via a STAT4-dependent pathway to stimulate survival, development of cytolytic function, and production of IFN-gamma...
  11. Villarino A, Tato C, Stumhofer J, Yao Z, Cui Y, Hennighausen L, et al. Helper T cell IL-2 production is limited by negative feedback and STAT-dependent cytokine signals. J Exp Med. 2007;204:65-71 pubmed several signal transducer and activator of transcription (STAT) family transcription factors, namely STAT5, STAT4, and STAT6...
  12. Poltorak A, Merlin T, Nielsen P, Sandra O, Smirnova I, Schupp I, et al. A point mutation in the IL-12R beta 2 gene underlies the IL-12 unresponsiveness of Lps-defective C57BL/10ScCr mice. J Immunol. 2001;167:2106-11 pubmed
    ..phosphorylation of Janus kinase 2, but, unlike the wild-type IL-12R, can no longer mediate phosphorylation of STAT4. Because the phosphorylation of STAT4 is a prerequisite for the IL-12-mediated induction of IFN-gamma, its absence ..
  13. 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
    b>Signal transducer and activator of transcription 4 (STAT4) and STAT6 are key factors in the specification of helper T cells; however, their direct roles in driving differentiation are not well understood...
  14. Berenson L, Gavrieli M, Farrar J, Murphy T, Murphy K. Distinct characteristics of murine STAT4 activation in response to IL-12 and IFN-alpha. J Immunol. 2006;177:5195-203 pubmed
    The role of type I IFN in Th1 development, STAT4 activation, and IFN-gamma production in murine T cells has remained unresolved despite extensive examination...
  15. Longman R, Braun D, Pellegrini S, Rice C, Darnell R, Albert M. Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-alpha/beta on antigen cross-presentation. Blood. 2007;109:1113-22 pubmed
    ..STAT1 in response to IFN-alpha/beta, whereas exposure of mature DCs to IFN-alpha/beta results in signaling via STAT4. Microarray analysis revealed numerous transcriptional changes resulting from the altered signaling...
  16. Holz A, Bot A, Coon B, Wolfe T, Grusby M, von Herrath M. Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence. J Immunol. 1999;163:5374-82 pubmed
    The role of the STAT4 signaling pathway in autoimmune diabetes was investigated using the rat insulin promoter lymphocytic choriomeningitis virus model of virally induced autoimmune diabetes...
  17. Thierfelder W, van Deursen J, Yamamoto K, Tripp R, Sarawar S, Carson R, et al. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996;382:171-4 pubmed
    ..b>Stat4 was initially cloned as a result of its homology with Stat1 (refs 4, 5) and is widely expressed, although it is ..
  18. Imada K, Leonard W. The Jak-STAT pathway. Mol Immunol. 2000;37:1-11 pubmed
    ..Moreover, the recent discovery of the CIS/SOCS/JAB/SSI family of inhibitors has contributed to understanding how this pathway is negatively regulated. ..
  19. Ouyang W, Ranganath S, Weindel K, Bhattacharya D, Murphy T, Sha W, et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity. 1998;9:745-55 pubmed
    ..Here, we show that loss of GATA-3 expression by developing Th1 cells requires IL-12 signaling through Stat4 and does not simply result from an absence of IL-4...
  20. Freudenberg M, Merlin T, Kalis C, Chvatchko Y, Stübig H, Galanos C. Cutting edge: a murine, IL-12-independent pathway of IFN-gamma induction by gram-negative bacteria based on STAT4 activation by Type I IFN and IL-18 signaling. J Immunol. 2002;169:1665-8 pubmed
    ..pathway is based on a synergism of IFN-alphabeta and IL-18, and is independent of IL-12 signaling yet dependent on STAT4. In contradiction to current dogma, we show further that IFN-alphabeta alone induces tyrosine phosphorylation of ..
  21. Wurster A, Tanaka T, Grusby M. The biology of Stat4 and Stat6. Oncogene. 2000;19:2577-84 pubmed
    ..Stat6 and Stat4 are two STAT family members that specifically mediate signals that emanate from the IL-4 and IL-12 receptors, ..
  22. Stamm L, Satoskar A, Ghosh S, David J, Satoskar A. STAT-4 mediated IL-12 signaling pathway is critical for the development of protective immunity in cutaneous leishmaniasis. Eur J Immunol. 1999;29:2524-9 pubmed
    Recent studies have demonstrated that two IL-12 signaling pathways, a STAT 4 - dependent and STAT4 - independent, are involved in the development of a Th1-like response...
  23. Mukasa R, Balasubramani A, Lee Y, Whitley S, Weaver B, Shibata Y, et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity. 2010;32:616-27 pubmed publisher
    ..but were rapidly reversed downstream of IL-12-induced silencing of the Rorc gene by the transcription factors STAT4 and T-bet...
  24. Saraiva M, Christensen J, Veldhoen M, Murphy T, Murphy K, O GARRA A. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity. 2009;31:209-19 pubmed publisher
    ..high T cell receptor (TCR) ligation, sustained ERK1 and ERK2 MAP kinases phosphorylation, and IL-12-induced STAT4 transcription factor activation...
  25. Shaw M, Freeman G, Scott M, Fox B, Bzik D, Belkaid Y, et al. Tyk2 negatively regulates adaptive Th1 immunity by mediating IL-10 signaling and promoting IFN-gamma-dependent IL-10 reactivation. J Immunol. 2006;176:7263-71 pubmed
    ..Thus, Tyk2 can be viewed as a dual-function Jak, mediating both pro and anti-inflammatory cytokine responses. ..
  26. Zhong Z, Wen Z, Darnell J. Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc Natl Acad Sci U S A. 1994;91:4806-10 pubmed
    ..While Stat1 and Stat3 are widely expressed, Stat4 expression is restricted to testis, thymus, and spleen...
  27. Raman K, Kaplan M, Hogaboam C, Berlin A, Lukacs N. STAT4 signal pathways regulate inflammation and airway physiology changes in allergic airway inflammation locally via alteration of chemokines. J Immunol. 2003;170:3859-65 pubmed
    Mice homozygous for the STAT4-null mutation were sensitized to cockroach Ag, challenged intratracheally 21 days later, and compared with STAT4-competent allergic mice...
  28. Afkarian M, Sedy J, Yang J, Jacobson N, Cereb N, Yang S, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells. Nat Immunol. 2002;3:549-57 pubmed
    ..through signal transducer and activator of transcription 1 (STAT1) and interleukin-12 (IL-12) signaling through STAT4 activation...
  29. Kaplan M, Sun Y, Hoey T, Grusby M. Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature. 1996;382:174-7 pubmed
    ..b>STAT4 is one member of this family, and is activated only in response to the cytokine interleukin (IL)-12 (refs 5, 6)...
  30. Cai G, Radzanowski T, Villegas E, Kastelein R, Hunter C. Identification of STAT4-dependent and independent mechanisms of resistance to Toxoplasma gondii. J Immunol. 2000;165:2619-27 pubmed
    ..To identify the transcription factors involved in this mechanism of resistance, mice deficient in STAT4, a protein involved in IL-12 signaling, were infected with T. gondii and their immune responses were analyzed...
  31. Kaplan M, Whitfield J, Boros D, Grusby M. Th2 cells are required for the Schistosoma mansoni egg-induced granulomatous response. J Immunol. 1998;160:1850-6 pubmed
    ..mansoni ova in Stat4- and Stat6-deficient mice, which lack Th1 and Th2 cells, respectively...
  32. Chowdhary V, Tilahun A, Clark C, Grande J, Rajagopalan G. Chronic exposure to staphylococcal superantigen elicits a systemic inflammatory disease mimicking lupus. J Immunol. 2012;189:2054-62 pubmed publisher
    ..The absence of disease in STAT4-deficient, as well as IFN-?-deficient, HLA-DQ8 mice suggested the pathogenic role of Th1-type cytokines, IL-12 and ..
  33. Klose C, Kiss E, Schwierzeck V, Ebert K, Hoyler T, d Hargues Y, et al. A T-bet gradient controls the fate and function of CCR6-ROR?t+ innate lymphoid cells. Nature. 2013;494:261-5 pubmed publisher
  34. Wilson D, Matthews S, Yap G. IL-12 signaling drives CD8+ T cell IFN-gamma production and differentiation of KLRG1+ effector subpopulations during Toxoplasma gondii Infection. J Immunol. 2008;180:5935-45 pubmed
  35. Ota N, Brett T, Murphy T, Fremont D, Murphy K. N-domain-dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation. Nat Immunol. 2004;5:208-15 pubmed
    The N-terminal protein interaction domain (N-domain) of the signal transducer and activator of transcription-4 (STAT4) is believed to stabilize interactions between two phosphorylated STAT4 dimers to form STAT4 tetramers...
  36. Balasubramani A, Shibata Y, Crawford G, Baldwin A, Hatton R, Weaver C. Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli. Immunity. 2010;33:35-47 pubmed publisher
    ..We have mapped interactions of three trans-acting factors-NF-kappaB, STAT4, and T-bet-with cis elements in the Ifng locus...
  37. Hwang I, Scott J, Kakarla T, Duriancik D, Choi S, Cho C, et al. Activation mechanisms of natural killer cells during influenza virus infection. PLoS ONE. 2012;7:e51858 pubmed publisher
    ..flu infection, STAT1 activation in NK cells was completely dependent on direct type I IFN signaling, whereas STAT4 activation was only partially dependent...
  38. Rocha F, Schleicher U, Mattner J, Alber G, Bogdan C. Cytokines, signaling pathways, and effector molecules required for the control of Leishmania (Viannia) braziliensis in mice. Infect Immun. 2007;75:3823-32 pubmed
    ..mexicana, mice deficient for interleukin-12 or its key signaling molecule, signal transducer and activator of transcription 4, rapidly succumbed to severe visceral leishmaniasis...
  39. Ueno T, Habicht A, Clarkson M, Albin M, Yamaura K, Boenisch O, et al. The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model. J Clin Invest. 2008;118:742-51 pubmed publisher
    ..TIM-1-specific antibody treatment was more effective in Th1-type cytokine-deficient Stat4(-/-) recipients as compared with Th2-type cytokine-deficient Stat6(-/-) recipients...
  40. Bell B, Kitajima M, Larson R, Stoklasek T, Dang K, Sakamoto K, et al. The transcription factor STAT5 is critical in dendritic cells for the development of TH2 but not TH1 responses. Nat Immunol. 2013;14:364-71 pubmed publisher
    ..Our results show that the TSLP-STAT5 axis in DCs is a critical component for the promotion of type 2 immunity at barrier surfaces. ..
  41. Zhu J, Jankovic D, Oler A, Wei G, Sharma S, Hu G, et al. The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity. 2012;37:660-73 pubmed publisher
    ..By contrast, T-bet and the transcription factor Stat4 were critical for IFN-γ production whereas IFN-γ signaling was dispensable for inducing IFN-γ...
  42. Wang W, Ostlie N, Conti Fine B, Milani M. The susceptibility to experimental myasthenia gravis of STAT6-/- and STAT4-/- BALB/c mice suggests a pathogenic role of Th1 cells. J Immunol. 2004;172:97-103 pubmed
    ..The STAT4 and STAT6 proteins, which mediate intracellular cytokine signaling, are important for differentiation of Th1 and ..
  43. Deng J, Zeng X, Newstead M, Moore T, Tsai W, Thannickal V, et al. STAT4 is a critical mediator of early innate immune responses against pulmonary Klebsiella infection. J Immunol. 2004;173:4075-83 pubmed
    ..IL-12, a key T1 cytokine in innate immunity, signals through STAT4. Thus, understanding how STAT4 mediates pulmonary immune responses against bacterial pathogens will have important ..
  44. Baumann C, Bonilla W, Fröhlich A, Helmstetter C, Peine M, Hegazy A, et al. T-bet- and STAT4-dependent IL-33 receptor expression directly promotes antiviral Th1 cell responses. Proc Natl Acad Sci U S A. 2015;112:4056-61 pubmed publisher
    ..ST2 expression on virus-specific Th1 cells depended on the Th1-associated transcription factors T-bet and STAT4. ST2 deficiency resulted in a T-cell-intrinsic impairment of LCMV-specific Th1 effector responses in both mixed ..
  45. Simovic M, Ballard B, Gray K, Stain S. The STAT4 and STAT6 pathways in pancreatitis-associated lung injury. J Surg Res. 2007;137:10-5 pubmed
    ..We examined the roles of STAT4 and STAT6 in lung injury after caerulein-induced severe acute pancreatitis...
  46. Yap G, Ortmann R, Shevach E, Sher A. A heritable defect in IL-12 signaling in B10.Q/J mice. II. Effect on acute resistance to Toxoplasma gondii and rescue by IL-18 treatment. J Immunol. 2001;166:5720-5 pubmed
    ..resistance and IFN-gamma production defects are determined by a single autosomal recessive locus distinct from the Stat4 gene...
  47. Vinkemeier U, Moarefi I, Darnell J, Kuriyan J. Structure of the amino-terminal protein interaction domain of STAT-4. Science. 1998;279:1048-52 pubmed
    ..Mutagenesis of an invariant tryptophan residue at the heart of this interface abolished cooperative DNA binding by the full-length protein in vitro and reduced the transcriptional response after cytokine stimulation in vivo. ..
  48. Herold K, Lu J, Rulifson I, Vezys V, Taub D, Grusby M, et al. Regulation of C-C chemokine production by murine T cells by CD28/B7 costimulation. J Immunol. 1997;159:4150-3 pubmed
    ..When T cell costimulation was provided by IL-2, MIP-1alpha was not enhanced. Studies with IL-2, IL-4, STAT4, and STAT6 knock-out mice suggested that chemokine production is controlled by pathways different from those ..
  49. Riella L, Ueno T, Batal I, De Serres S, Bassil R, Elyaman W, et al. Blockade of Notch ligand ?1 promotes allograft survival by inhibiting alloreactive Th1 cells and cytotoxic T cell generation. J Immunol. 2011;187:4629-38 pubmed publisher
    ..To our knowledge, these data demonstrate for the first time an important role of Delta1 in alloimmunity, identifying Delta1 ligand as a potential novel target for immunomodulation in transplantation. ..
  50. Ranatunga D, Hedrich C, Wang F, McVicar D, Nowak N, Joshi T, et al. A human IL10 BAC transgene reveals tissue-specific control of IL-10 expression and alters disease outcome. Proc Natl Acad Sci U S A. 2009;106:17123-8 pubmed publisher
    ..Thus, the hIL10BAC mouse is a model of human gene structure and function revealing tissue-specific regulatory requirements for IL-10 expression which impacts disease outcomes. ..
  51. Shi H, Grusby M, Nagler Anderson C. Orally induced peripheral nonresponsiveness is maintained in the absence of functional Th1 or Th2 cells. J Immunol. 1999;162:5143-8 pubmed
    ..In the mucosa, however, the absence of Th1 and Th2 cytokines can markedly affect this response, perhaps by regulation of TGF-beta-secreting cells. ..
  52. Pellegrini S, Dusanter Fourt I. The structure, regulation and function of the Janus kinases (JAKs) and the signal transducers and activators of transcription (STATs). Eur J Biochem. 1997;248:615-33 pubmed
    ..Recent findings have suggested that the interdependence of JAKs and STATs might not be absolute as originally thought. ..
  53. Copeland N, Gilbert D, Schindler C, Zhong Z, Wen Z, Darnell J, et al. Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics. 1995;29:225-8 pubmed
    ..The data suggest that the family has arisen via a tandem duplication of the ancestral locus, followed by dispersion of the linked loci to different mouse chromosomes. ..