Genomes and Genes
stat4 transcription factor
Summary: A signal transducer and activator of transcription that mediates cellular responses to INTERLEUKIN-12 in T-LYMPHOCYTES. Stat4 is an important signaling molecule for differentiation in TH1 CELLS.
- 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. ..
- Yang W, Ng P, Zhao M, Hirankarn N, Lau C, Mok C, et al. Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese. Genes Immun. 2009;10:219-26 pubmed publisher..36, OR=1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific. ..
- Orozco G, Alizadeh B, Delgado Vega A, Gonzalez Gay M, Balsa A, Pascual Salcedo D, et al. Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. Arthritis Rheum. 2008;58:1974-80 pubmed publisher..25 (95% CI 1.19-1.33) (P = 1 x 10(-5)). Our findings indicate an association between the STAT4 polymorphism rs7574865 and RA in 3 different populations, from Spain, Sweden, and The Netherlands, thereby confirming previous data. ..
- Remmers E, Plenge R, Lee A, Graham R, Hom G, Behrens T, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med. 2007;357:977-86 pubmed..A haplotype of STAT4 is associated with increased risk for both rheumatoid arthritis and systemic lupus erythematosus, suggesting a shared pathway for these illnesses. ..
- Xu Z, Duan B, Croker B, Morel L. STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus. Clin Immunol. 2006;120:189-98 pubmed..TC mouse. In contrast, the IL-4/STAT6 pathway regulates only a subset of disease markers that did not affect renal pathology. ..
- 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..T cell receptor (TCR) ligation, sustained ERK1 and ERK2 MAP kinases phosphorylation, and IL-12-induced STAT4 transcription factor activation...
- Lund R, Chen Z, Scheinin J, Lahesmaa R. Early target genes of IL-12 and STAT4 signaling in th cells. J Immunol. 2004;172:6775-82 pubmed..Importantly, addition of exogenous IFN-gamma into Th1 cell cultures of STAT4-knockout cells restored the defect in IFN-gamma production further demonstrating the critical role of IFN-gamma in early Th1 differentiation. ..
- Piotrowski P, Lianeri M, Wudarski M, Olesinska M, Jagodziński P. Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population. Mol Biol Rep. 2012;39:8861-6 pubmed publisher..665 (1.380-5.147, p = 0.0028), (p (corr) = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease. ..
- Gao B. Cytokines, STATs and liver disease. Cell Mol Immunol. 2005;2:92-100 pubmed..This article reviews the biological significance of STAT1, 2, 3, 4, 5, 6 in hepatic functions and diseases...
- Harris D, Goodrich S, Gerth A, Peng S, Lund F. Regulation of IFN-gamma production by B effector 1 cells: essential roles for T-bet and the IFN-gamma receptor. J Immunol. 2005;174:6781-90 pubmed
- Lee H, Park H, Yang S, Kim D, Park Y. STAT4 polymorphism is associated with early-onset type 1 diabetes, but not with late-onset type 1 diabetes. Ann N Y Acad Sci. 2008;1150:93-8 pubmed publisher..Recognizing that only the early-onset cases might represent the true autoimmune T1D in Asian populations, we see that STAT4 alleles and haplotype might influence cytokine signaling and, therefore, development of T1D. ..
- 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..Overall, these results suggest an important role for STAT4 in regulating Treg-cell development. ..
- Harley J, Alarcon Riquelme M, Criswell L, Jacob C, Kimberly R, Moser K, et al. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat Genet. 2008;40:204-10 pubmed publisher..Our results show that numerous genes, some with known immune-related functions, predispose to SLE. ..
- Rutz S, Janke M, Kassner N, Hohnstein T, Krueger M, Scheffold A. Notch regulates IL-10 production by T helper 1 cells. Proc Natl Acad Sci U S A. 2008;105:3497-502 pubmed publisher..This pathway may provide unique opportunities for therapeutic intervention in Th1-driven immune diseases and for Th1-associated vaccination strategies. ..
- Taylor K, Remmers E, Lee A, Ortmann W, Plenge R, Tian C, et al. Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus. PLoS Genet. 2008;4:e1000084 pubmed publisher..We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease. ..
- 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
- Nordmark G, Kristjansdottir G, Theander E, Eriksson P, Brun J, Wang C, et al. Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome. Genes Immun. 2009;10:68-76 pubmed publisher..43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS. ..
- Su Y, Zhao Y, Liu X, Guo J, Jiang Q, Liu X, et al. Variation in STAT4 is associated with systemic lupus erythematosus in Chinese Northern Han population. Chin Med J (Engl). 2010;123:3173-7 pubmed..The SNP rs7574865 in STAT4 is strongly associated with risk of SLE in the Chinese Northern Han population. The TT genotype and T allele in STAT4 rs7574869 are susceptibility factors for SLE, especially for male SLE patients. ..
- 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..Our study revealed redundancy and synergy among several Th1 cell-inducing pathways in regulating the expression of T-bet and IFN-Î³, and a critical role of T-bet in suppressing an endogenous Th2 cell-associated program. ..
- 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..Some induced genes correlate with specific functions including the ability of Stat4beta, but not Stat4alpha, to mediate IL-12-stimulated proliferation. Thus, Stat4alpha and Stat4beta have distinct roles in mediating responses to IL-12. ..
- Watford W, Hissong B, Bream J, Kanno Y, Muul L, O Shea J. Signaling by IL-12 and IL-23 and the immunoregulatory roles of STAT4. Immunol Rev. 2004;202:139-56 pubmed..In contrast, IL-23 promotes end-stage inflammation. Targeting IL-12, IL-23, and their downstream signaling elements would therefore be logical strategies for the treatment of immune-mediated diseases. ..
- Mudter J, Weigmann B, Bartsch B, Kiesslich R, Strand D, Galle P, et al. Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases. Am J Gastroenterol. 2005;100:64-72 pubmed..Furthermore, the IL-6/STAT-3 rather than the IFN-gamma/STAT-1 signaling pathway emerges as a key target for the development of future therapeutic concepts in IBD. ..
- Grant L, Yao Z, Hedrich C, Wang F, Moorthy A, Wilson K, et al. Stat4-dependent, T-bet-independent regulation of IL-10 in NK cells. Genes Immun. 2008;9:316-27 pubmed publisher..These findings highlight tissue- and receptor-specific IL-10 regulatory mechanisms, which may be part of an early feedback loop. ..
- Kim S, Gunst K, Sarvetnick N. STAT4/6-dependent differential regulation of chemokine receptors. Clin Immunol. 2006;118:250-7 pubmed..These results provide the basis for STAT-dependent differential regulation of chemokine receptors in Th subsets. ..
- Chen Z, Laurence A, Kanno Y, Pacher Zavisin M, Zhu B, Tato C, et al. Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A. 2006;103:8137-42 pubmed..We conclude that Socs3 is an essential negative regulator of IL-23 signaling, inhibition of which constrains the generation of Th17 differentiation. ..
- Strengell M, Matikainen S, Sirén J, Lehtonen A, Foster D, Julkunen I, et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells. J Immunol. 2003;170:5464-9 pubmed..IL-18, however, activated the binding of NF-kappa B to the IFN-gamma promoter NF-kappa B site. Our results suggest that both IL-15 and IL-21 have an important role in activating the NK cell-associated innate immune response. ..
- 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..These findings provide a basis for understanding how inhibition of IFN-gamma signaling enhances development of pathogenic T(H)-17 effector cells that can exacerbate autoimmunity. ..
- Rueda B, Broen J, Simeon C, Hesselstrand R, Diaz B, Suarez H, et al. The STAT4 gene influences the genetic predisposition to systemic sclerosis phenotype. Hum Mol Genet. 2009;18:2071-7 pubmed publisher..36-1.74; P < 0.0001). Our data show a strong and reproducible association of the STAT4 gene with the genetic predisposition to lcSSc suggesting that this gene seems to be one of the genetic markers influencing SSc phenotype. ..
- Kobayashi S, Ikari K, Kaneko H, Kochi Y, Yamamoto K, Shimane K, et al. Association of STAT4 with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Japanese population. Arthritis Rheum. 2008;58:1940-6 pubmed publisher..We conclude that STAT4 is associated with RA and SLE in the Japanese. Our results indicate that STAT4 is a common genetic risk factor for autoimmune diseases, with similar strength across major racial groups. ..
- Martinez A, Varadé J, Marquez A, Cenit M, Espino L, Perdigones N, et al. Association of the STAT4 gene with increased susceptibility for some immune-mediated diseases. Arthritis Rheum. 2008;58:2598-602 pubmed publisher..83, OR 1.02, 95% CI 0.82-1.28). The STAT4 gene is emerging as a novel common risk factor for diverse complex diseases. ..
- Sugimoto N, Nakahira M, Ahn H, Micallef M, Hamaoka T, Kurimoto M, et al. Differential requirements for JAK2 and TYK2 in T cell proliferation and IFN-gamma production induced by IL-12 alone or together with IL-18. Eur J Immunol. 2003;33:243-51 pubmed
- Korman B, Kastner D, Gregersen P, Remmers E. STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep. 2008;8:398-403 pubmed..In concert with the identification of other disease-associated loci, elucidating how the variant form of STAT4 modulates immune function should lead to an improved understanding of the pathophysiology of autoimmunity. ..
- Brigl M, Tatituri R, Watts G, Bhowruth V, Leadbetter E, Barton N, et al. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med. 2011;208:1163-77 pubmed publisher..These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections. ..
- Zervou M, Vazgiourakis V, Yilmaz N, Kontaki E, Trouw L, Toes R, et al. TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey. Hum Immunol. 2011;72:1210-3 pubmed publisher..These data highlight the importance of comparative studies in different populations to confirm the previously detected genetic associations. ..
- Nishikomori R, Usui T, Wu C, Morinobu A, O Shea J, Strober W. Activated STAT4 has an essential role in Th1 differentiation and proliferation that is independent of its role in the maintenance of IL-12R beta 2 chain expression and signaling. J Immunol. 2002;169:4388-98 pubmed..This implies that STAT4 is an essential element in the early events of Th1 differentiation. ..
- 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..This suggests that STAT4 binding to target genes, while critical, is not the only determinant for STAT4-dependent gene programming during Th1 differentiation. ..
- 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..These data provide evidence for a molecular switch in signaling pathways concomitant with DC maturation that offers a novel mechanism by which DCs modulate the integration of signals from the surrounding environment. ..
- 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
- Sigurdsson S, Nordmark G, Garnier S, Grundberg E, Kwan T, Nilsson O, et al. A risk haplotype of STAT4 for systemic lupus erythematosus is over-expressed, correlates with anti-dsDNA and shows additive effects with two risk alleles of IRF5. Hum Mol Genet. 2008;17:2868-76 pubmed publisher..82-fold risk of SLE with two independent risk alleles of the IRF5 (interferon regulatory factor 5) gene. ..
- Svenungsson E, Gustafsson J, Leonard D, Sandling J, Gunnarsson I, Nordmark G, et al. A STAT4 risk allele is associated with ischaemic cerebrovascular events and anti-phospholipid antibodies in systemic lupus erythematosus. Ann Rheum Dis. 2010;69:834-40 pubmed publisher..The results imply that a genetic predisposition is an important and previously unrecognised risk factor for ICVD in SLE, and that aPLs may be one underlying mechanism. ..
- O Sullivan A, Chang H, Yu Q, Kaplan M. STAT4 is required for interleukin-12-induced chromatin remodeling of the CD25 locus. J Biol Chem. 2004;279:7339-45 pubmed..Thus, these results provide a model for STAT4-dependent gene induction and a mechanism for cytokine-induced expression of the CD25 gene. ..
- Durali D, de Goër de Herve M, Giron Michel J, Azzarone B, Delfraissy J, Taoufik Y. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment. Blood. 2003;102:4084-9 pubmed..IL-12 therefore initiates a cascade of events in B cells, including STAT4 activation, IL-12Rbeta2 up-regulation, IFN-gamma production, and T-bet up-regulation, potentially leading to Th1-like differentiation. ..
- Robertson M, Chang H, Pelloso D, Kaplan M. Impaired interferon-gamma production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma. Blood. 2005;106:963-70 pubmed
- Chung S, Taylor K, Graham R, Nititham J, Lee A, Ortmann W, et al. Differential genetic associations for systemic lupus erythematosus based on anti-dsDNA autoantibody production. PLoS Genet. 2011;7:e1001323 pubmed publisher..Lack of strong SNP associations may suggest that other types of genetic variation or non-genetic factors such as environmental exposures have a greater impact on susceptibility to anti-dsDNA - SLE. ..
- Nakayamada S, Kanno Y, Takahashi H, Jankovic D, Lu K, Johnson T, et al. Early Th1 cell differentiation is marked by a Tfh cell-like transition. Immunity. 2011;35:919-31 pubmed publisher..Our data argue that Tfh and Th1 cells share a transitional stage through the signal mediated by STAT4, which promotes both phenotypes. However, T-bet represses Tfh cell functionalities, promoting full Th1 cell differentiation. ..
- Mo C, Chearwae W, O Malley J, Adams S, Kanakasabai S, Walline C, et al. Stat4 isoforms differentially regulate inflammation and demyelination in experimental allergic encephalomyelitis. J Immunol. 2008;181:5681-90 pubmed..This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE. ..
- Zervou M, Mamoulakis D, Panierakis C, Boumpas D, Goulielmos G. STAT4: a risk factor for type 1 diabetes?. Hum Immunol. 2008;69:647-50 pubmed publisher..These findings suggest that this variant form of STAT4 may have a putative key role in the development of a variety of autoimmune diseases, probably because of signaling defects that it causes in the IL-12 pathway. ..
- 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..Thus, type 1 IFNs, in addition to interleukin-12, provide pathways for innate regulation of adaptive immunity, and their immunoregulatory functions are controlled by modulating the activity of individual STATs...
- Chakrabarti S, Wen Y, Dobrian A, Cole B, Ma Q, Pei H, et al. Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats. Am J Physiol Endocrinol Metab. 2011;300:E175-87 pubmed publisher..In 3T3-L1 adipocytes, LSF abrogated the inflammatory response induced by LO products. Thus, therapeutic agents reducing LO or STAT4 activation may provide novel tools to reduce obesity-induced inflammation. ..