Inteferons pen the JAK–STAT pathway

Schindler, Christian; Plumlee, Courtney R.

doi:10.1016/j.semcdb.2008.08.010

Cited by 225 publications

(210 citation statements)

References 158 publications

(190 reference statements)

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“…Finally, the IFN-driven resistance to GCHV infection was enhanced in Stat1-WT-transfected cells but a relief of viral replication was observed in the context of the transfection of Stat1-C. Considering that Stat1 is involved in IFN-induced Jak-Stat pathway (Platanias, 2005;Schindler and Plumlee, 2008;Stark et al, 1998), these findings implicate that from lower fish to higher mammals, the Stat1 signaling pathway is considerably conserved in IFN-induced downstream gene transcription and host antiviral state.…”

Section: Discussionmentioning

confidence: 77%

“…However, transfection of Stat1 alone is not sufficient to initiate the transcription of ISGs. This can be explained by the finding in mammals that Stat1 is generally a latent cytoplasmic transcription factor and the activation of Stat1 is required for IFN signaling transmission (Platanias, 2005;Schindler and Plumlee, 2008;Stark et al, 1998). Interestingly, two Stat1 genes are found in zebrafish (Stein et al, 2007) and three in Atlantic salmon (Skjesol et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…scriptional activation and generation of protein products that are ultimately required for establishment of host antiviral state (Schindler and Plumlee, 2008). The key role of Stat1 in IFN signaling cascade was further delineated by two reports in which Stat1 null mice exhibit a complete lack of responsiveness to either type I IFN or type II IFN and are highly sensitive to infection by microbial pathogens and viruses (Durbin et al, 1996;Meraz et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Fish virus-induced interferon exerts antiviral function through Stat1 pathway

Zhang

Liu

et al. 2010

Molecular Immunology

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fish virus-induced interferon exerts antiviral function through Stat1 pathway

Zhang

Liu

et al. 2010

Molecular Immunology

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“…JAK2 associates constitutively with IL23R, and STAT3 is recruited to the complex on IL23R stimulation (13). JAK proteins generally associate through their 4.1, ezrin, radixin, moesin (FERM) domain with membraneproximal regions of cytokine receptors (32). R381 is in the proximal IL23R cytoplasmic tail at the fifth amino acid from the putative transmembrane region, and it is conserved between species.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

Sarin

Abraham

2011

Proc. Natl. Acad. Sci. U.S.A.

178

124

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The SNP (c.1142G > A;p.R381Q) in the IL-23 receptor (IL23R) confers protection from multiple inflammatory diseases, representing one of the most significant human genetic polymorphisms in autoimmunity. We, therefore, sought to define the functional consequences of this clinically significant variant. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percentage of circulating Th17 and Tc17 cells. Furthermore, CD8+ T cells from R381Q IL23R individuals showed decreased IL-23-dependent expansion and signal transducer and activator of transcription 3 (STAT3) activation compared with WT CD8+ T cells. Importantly, cells transfected with the IL23R glutamine variant show decreased IL-23-mediated signaling compared with the IL23R arginine allele. Our results show that the R381Q IL23R variant leads to selective, potentially desirable, loss of function alterations in primary human CD4+ and CD8+ T cells, resulting in highly significant protection against autoimmunity.cytokines | Crohn's disease | ulcerative colitis | psoriasis T he IL-23/Th17 pathway is critical for optimal microbial defenses (1, 2); however, disregulation of this pathway can lead to inflammation (3-9). The SNP (c.1142G > A; p.R381Q) in IL-23 receptor (IL23R) confers protection from inflammatory diseases, including ankylosing spondylitis, psoriasis, and inflammatory bowel disease (10-12); it represents one of the most significant human genetic polymorphisms in autoimmunity. On binding to the IL23R complex, IL-23 mediates its effects by signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and NF-κB pathways (13,14). IL-23 modulates responses in multiple cell populations, including differentiation and maintenance of CD4+ Th17 (6, 15-17) and CD8+ Tc17 cells (18)(19)(20)(21).We considered that the disease-protective R381Q IL23R may result in a loss of function, leading to decreased IL-23/Th17 pathway cytokine production, or a gain of function, leading to enhanced microbial clearance. We find that CD4+CD45RO+ and CD8+ T cells from healthy R381Q IL23R carriers show decreased IL-23-dependent IL-17 and IL-22 production relative to WT IL23R individuals. This was associated with a lower percent of circulating Th17 and Tc17 cells. Furthermore, R381Q CD8+ T cells showed decreased IL-23-and STAT3-dependent expansion and STAT3 activation compared with WT cells. Our results indicate that the protective R381Q IL23R variant leads to selective loss of function in primary human CD4+ and CD8+ T cells. ResultsMemory CD4+ T Cells from R381Q IL23R Individuals Show Decreased IL-23-Mediated Th17 Cytokine Production on in Vitro Stimulation. To define the role of the disease-protective R381Q IL23R polymorphism, we genotyped 650 healthy individuals and identified 48 individuals carrying the minor glutamine allele, consistent with prior estimates of a 7% allele frequency (11). WT individuals are...

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“…STAT proteins contain seven conserved structural and functional domains (Fig. 1a) (Schindler and Plumlee 2008).…”

Section: The Family Of Stat Transcription Factorsmentioning

confidence: 99%

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

et al. 2012

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Signal transducers and activators of transcription (STAT) proteins were described as a family of latent cytosolic transcription factors whose activation is dependent on phosphorylation via growth factor-and cytokine-membrane receptors including interferon and interleukin, or by nonreceptor intracellular tyrosine kinases, including Src. A vast majority of natural substances are capable of modulating mitogenic signals, cell survival, apoptosis, cell cycle regulation, angiogenesis as well as processes involved in metastasis development. The inhibition of STAT3 phosphorylation by natural and dietary compounds leads to decreased protein expression of STAT3 targets essentially involved in regulation of the cell cycle and apoptotic cell death. This review details the cell signaling pathways involving STAT transcription factors as well as the corresponding compounds from nature able to interfere with this regulatory system in human cancer.The family of STAT transcription factors Structure and function STAT (signal transducers and activators of transcription) proteins were originally described as a family of cytoplasmic transcription factors. In mammals, seven members of this family, each consisting of 750-900 amino acids, have been identified: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. These transcription factors act as dimers (homo-or hetero-dimers), and their activation is dependent on their phosphorylation or via membrane receptors stimulated by either extracellular factors, including interferon (IFN) and interleukin (IL-6), or by intracellular kinases independent of receptors, including Src. Activation of STATs is usually transient and highly regulated. STAT proteins contain seven conserved structural and functional domains ( First, the amino terminal NH 2 domain is involved in the dimerization of STAT proteins and in the stabilization of the interaction established between these dimers and DNA response elements (Braunstein et al. 2003;Mertens et al. 2006). The coiled-coil domain is responsible for controlling the process of import and export of proteins into and from the nucleus (Schindler et al. 2007). The domain that binds DNA, or the DBD (DNA binding domain), is involved in the physical interaction with STAT3-response elements in the promoters of target genes. With the exception of STAT2, all activated STAT homodimers bind directly to a palindromic sequence, the GAS (IFN-gammaactivated site), TTTCCNGGAAA (Becker et al. 1998). The ''linker'' domain localizes the active dimer to the DNA binding site. The transcriptional activation domain (TAD) contains sites of phosphorylation of serine residues that allow the recruitment of coactivators such as RNA polymerase II, histone acetyltransferase (HAT) (Paulson et al. 2002), histone deacetylase (HDAC) (Rascle et al. 2003) and chromatin modification complexes.Finally, two sites are particularly critical for the activity of STAT. These are the SH2 domain (Src homology 2, amino acids 575-680), which is linked to the DBD by the linker domain, and a conser...

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Inteferons pen the JAK–STAT pathway

Cited by 225 publications

References 158 publications

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

Fish virus-induced interferon exerts antiviral function through Stat1 pathway

Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

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