Distinct requirements for the naturally occurring splice forms Stat4  and Stat4  in IL-12 responses

Hoey, Timothy; Zhang, Shangming; Schmidt, Nathan W.; Yu, Qing; Ramchandani, Shyam; Xu, Xin; Naeger, Lisa K.; Sun, Ya L.; Kaplan, Mark H.

doi:10.1093/emboj/cdg393

Cited by 84 publications

(102 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…STAT4 may interact with other transcription factors at a promoter through several domains, including the C-terminal "transactivation domain." However, both STAT4 isoforms, STAT4␣ and STAT4␤ (16), the latter of which lacks the C-terminal 40 amino acids encompassing the putative transcription activation domain, are able to activate transcription and mediate many IL-12 responses. This suggests that interactions of other transcription factors with the STAT4 transactivation domain are not required for all STAT4-dependent responses.…”

Section: Interleukin-12 (Il-12)mentioning

confidence: 99%

See 1 more Smart Citation

STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus

O'Sullivan

Chang²,

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Interleukin 1 is a pleiotropic cytokine produced from macrophages and dendritic cells, which induces several responses in T cells including increased proliferation, increased cytotoxic activity, and Th1 differentiation (1). IL-12 activates several signaling pathways that may mediate these biological activities including p38 MAPK and the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (2-5). Upon binding of IL-12, both chains of the IL-12 receptor (IL-12R␤1 and IL-12R␤2) heterodimerize and activate the associated JAKs, TYK2, and JAK2. The IL-12R␤2 chain is subsequently tyrosine phosphorylated and recruits STAT4 to a specific docking site where it is itself phosphorylated (6). The phosphorylated STAT4 monomers then homodimerize and translocate into the nucleus. STAT4 is required for many of the functions of IL-12 including the induction of IFN-␥ and the differentiation of Th1 cells (7,8).Once in the nucleus, STAT4 binds to a cognate binding sequence within IL-12 responsive genes to subsequently mediate activation of transcription (9 -11). Several IL-12 responsive genes that require STAT4 for transcriptional activation have been identified including IFN-␥ (7-9, 12), IL-18R␣ (13, 14), ERM (15) and IRF-1 (10, 11). STAT4 may interact with other transcription factors at a promoter through several domains, including the C-terminal "transactivation domain." However, both STAT4 isoforms, STAT4␣ and STAT4␤ (16), the latter of which lacks the C-terminal 40 amino acids encompassing the putative transcription activation domain, are able to activate transcription and mediate many IL-12 responses. This suggests that interactions of other transcription factors with the STAT4 transactivation domain are not required for all STAT4-dependent responses. Furthermore, the events that STAT4 initiates at a promoter, and the kinetics with which they occur have not been characterized.CD25 is the ␣ chain of the high affinity IL-2 receptor complex. CD25 is only expressed upon T cell activation, and expression is further modulated by IL-2 stimulation. Transcription of CD25 is regulated by multiple transcription factors that bind to elements termed positive regulatory regions (PRR) in the CD25 promoter and intronic regions. PRRI is located around 260 nucleotides upstream of the major transcription initiation sites in the mouse gene (Ϫ276 to Ϫ244 in human) (17-19) and binds NF-B and serum response factor (20). PR-RII is around Ϫ100 in the mouse gene (Ϫ137 to Ϫ64 in human) and binds . PRRIII, also known as the IL-2 responsive element (IL-2rE), is located Ϫ1306 to Ϫ1387 in the mouse gene (Ϫ3780 to Ϫ3703 in human), and one of the tandem STAT5 binding sites overlaps a binding site for . In the mouse gene, an additional regulatory element at Ϫ576 to Ϫ667 that contains binding sites for NFAT and AP-1 proteins is also required for T cell receptor-mediated induction of IL-2R␣ chain expression (27). Recently, two additional elements in the human gene have been identified, a CD28 responsive element (CD28rE) at Ϫ8.5 kB t...

show abstract

Section: Interleukin-12 (Il-12)mentioning

confidence: 99%

“…We wanted to investigate whether STAT4 was interacting with other transcription factors to mediate CD25 transcription. STAT4 is known to cooperatively interact with c-Jun to induce several genes such as IFN-␥ and IRF-1 (16,45).…”

Section: Upon Il-12 Stimulation the Association Of Stat4 To Prriii Anmentioning

confidence: 99%

STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus

O'Sullivan

Chang²,

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Recently, an increasing number of studies have used DNA microarrays to identify new factors involved in the Th1 and Th2 polarization in humans and mice (7)(8)(9)(10)(11)(12)(13)(14). However, all of these studies have focused on studying a limited number of primarily known genes.…”

mentioning

confidence: 99%

Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

Lund

Löytömäki

Naumanen

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Th cell subtypes, Th1 and Th2, are involved in the pathogenesis or progression of many immune-mediated diseases, such as type 1 diabetes and asthma, respectively. Defining the molecular networks and factors that direct Th1 and Th2 cell differentiation will help to understand the pathogenic mechanisms causing these diseases. Some of the key factors regulating this differentiation have been identified, however, they alone do not explain the process in detail. To identify novel factors directing the early differentiation, we have studied the transcriptomes of human Th1 and Th2 cells after 2, 6, and 48 h of polarization at the genome scale. Based on our current and previous studies, 288 genes or expressed sequence tags, representing ∼1–1.5% of the human genome, are regulated in the process during the first 2 days. These transcriptional profiles revealed genes coding for components of certain pathways, such as RAS oncogene family and G protein-coupled receptor signaling, to be differentially regulated during the early Th1 and Th2 cell differentiation. Importantly, numerous novel genes with unknown functions were identified. By using short-hairpin RNA knockdown, we show that a subset of these genes is regulated by IL-4 through STAT6 signaling. Furthermore, we demonstrate that one of the IL-4 regulated genes, NDFIP2, promotes IFN-γ production by the polarized human Th1 lymphocytes. Among the novel genes identified, there may be many factors that play a crucial role in the regulation of the differentiation process together with the previously known factors and are potential targets for developing therapeutics to modulate Th1 and Th2 responses.

show abstract

“…Interestingly, a similar functional difference between STAT4a and STAT4b subunits has been reported in mice, in which Stat4b was not as efficient as Stat4a in directly inducing IFNg gene expression. 19 Two hypotheses can be drawn from those results: either STAT4 may be activated after the ligation of type 1 IFN on IFNAR in parallel and independently of type 1 IFN-induced genes, as was previously suggested in mice and in humans, 20,21 or STAT4 could be an intermediate for induction of type 2 IFN (its classical role) and for inducing the expression of type 1 IFNinduced genes, as was recently suggested by Kariuki et al 9 This last hypothesis needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

et al. 2010

View full text Add to dashboard Cite

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor mainly activated by interleukin 12, which promotes the secretion of type 2 interferon (IFN) by T-helper 1 cells. We assessed the association of STAT4 gene polymorphism and primary Sjö gren's syndrome (pSS) and its functional relevance. We analyzed STAT4 rs7582694 polymorphism in an exploratory cohort of 186 pSS patients and 152 controls, and in a replication cohort of 192 pSS patients and 483 controls, all Caucasian. mRNA levels of STAT4a, STAT4b, STAT1, and the type 1 IFN-induced genes PKR, MX1 and IFITM1 were assessed in peripheral blood mononuclear cells (PBMCs) from 30 pSS patients. STAT4 rs7582694 C allele was associated with pSS in both cohorts (odds ratio (OR) 1.57, 95% confidence interval (CI) 1.27-1.93, P ¼ 2.3 Â 10 À5 ). The association was increased for homozygous subjects, which suggests a recessive effect of the STAT4 at-risk allele. STAT4a, STAT4b and STAT1 mRNA levels in PBMCs were not significantly associated with rs7582694 genotypes, however the mRNA levels of STAT4a and type 1 IFN-induced genes were strongly correlated: PKR (P ¼ 4 Â 10 À3 , r ¼ 0.51), MX1 (P ¼ 2 Â 10 À4 , r ¼ 0.63) and IFITM1 (P ¼ 8 Â 10 À3 , r ¼ 0.47), suggesting that STAT4 might be involved in not only type 2 IFN production but also in type 1 IFN-mediated effects.

show abstract

Distinct requirements for the naturally occurring splice forms Stat4 and Stat4 in IL-12 responses

Cited by 84 publications

References 64 publications

STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus

STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus

Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

STAT4 is a confirmed genetic risk factor for Sjögren's syndrome and could be involved in type 1 interferon pathway signaling

Contact Info

Product

Resources

About