Disease relevance of STAT4

• Depressed IL-12-mediated signal transduction in T cells from patients with Sézary syndrome is associated with the absence of IL-12 receptor beta 2 mRNA and highly reduced levels of STAT4 [1].
• Constitutive tyrosine and serine phosphorylation of STAT4 in T-cells transformed with HTLV-I [2].
• IL-12-dependent constitutive STAT4 activation was also observed in the Epstein-Barr virus (EBV)-transformed B-cell line RPMI 8866 that spontaneously produces IL-12 [3].
• Impaired interferon-gamma production as a consequence of STAT4 deficiency after autologous hematopoietic stem cell transplantation for lymphoma [4].
• 1. A significant association with one MS allele near STAT4 was shown and a cluster of SNPs in LD with the MS marker was associated with sarcoidosis [5].
• 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 [6].
• STAT4 and IRF5 act with additive effects in terms of susceptibility to both SSc and SSc-related fibrosing alveolitis [7].

High impact information on STAT4

• Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells [8].
• 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 [9].
• Mutations in the N-domain dimerization interface abolished assembly of nonphosphorylated STAT4 dimers and prevented STAT4 phosphorylation mediated by cytokine receptors [10].
• In some cases known pathways may be used, as in the dendritic cell subset 1 exerting TH1 polarization by interleukin 12 (IL-12) production and STAT4 activation [11].
• Expression of IL-12Rbeta2 alone, however, was insufficient to induce signal transducer and activator of transcription (Stat)4 activation in response to IL-12, whereas IFN-alpha/IFN-alphaR ligation resulted in Stat4 activation in both control and IL-12Rbeta1-deficient cells [12].

Chemical compound and disease context of STAT4

• Inhibition of STAT4 activation by lisofylline is associated with the protection of autoimmune diabetes [13].

Biological context of STAT4

• Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in human lymphocytes [14].
• Furthermore, we show that IL-12 stimulates formation of a DNA-binding complex that recognizes a DNA sequence previously shown to bind STAT proteins and that this complex contains STAT4 [14].
• Here, we show that activation of this receptor by IFN-lambda 1 can also inhibit cell proliferation and induce STAT4 phosphorylation, further extending functional similarities with type I IFNs [15].
• Transient expression of wild-type SPHK2 in T cell hybridoma augmented IL-12-induced STAT4-mediated transcriptional activation [16].
• This is the first observation linking STAT4 gene expression with a human disease and suggests that dysregulation of STAT4 expression may be significant to the development and/or progression of SS [1].

Anatomical context of STAT4

• In this report we demonstrate that IL-12 induces tyrosine phosphorylation of a recently identified STAT family member, STAT4, and show that STAT4 expression is regulated by T-cell activation [14].
• The unique activation of the STAT4-signaling pathway in NK cells may underlie the distinct functional effect of IL-2 on this cell population [17].
• However, unlike normal Th2 cells, SS cells also showed severely reduced levels of STAT4, suggesting that they have a depressed response to any inducer of the STAT4 signal transduction pathway, including IFN-alpha [1].
• STAT4 is a critical mediator of IL-12-stimulated gene regulation in T-helper type 1 (Th1) cell [2].
• However, human STAT1 is expressed ubiquitously, whereas human STAT4 is expressed in several tissues including spleen, heart, brain, peripheral blood cells, and testis [18].

Associations of STAT4 with chemical compounds

• Activation of STAT4 by IL-12 and IFN-alpha: evidence for the involvement of ligand-induced tyrosine and serine phosphorylation [19].
• Our aim was to investigate the effects of dexamethasone on STAT4 activation by IFN-beta and IL-12 in human T cell blasts [20].
• Moreover, IL-12 activation of STAT4 in human peripheral blood-derived T cells is not accompanied by stimulation of the Ras guanine nucleotide binding cycle or stimulation of MAPK Erk1,2 or initiation of the PI3K signaling pathways [21].
• We show that STAT4 has a unique peptide specificity and binds to the peptide sequence pYLPSNID (where pY represents phosphotyrosine) [22].
• A series of alanine replacements was performed in this phosphopeptide to elucidate which amino acids surrounding the pTyr800 residue are critical for STAT4 binding [23].

Physical interactions of STAT4

• We then investigated the role of Ik binding elements in the human STAT4 promoter using Jurkat T cells [24].
• To summarize, the site on the IL-12 receptor which binds STAT4 can be described as -T-X-X-G-pY(800)-L-, where the core G-pY(800)-L motif is critical for the binding; the threonine at the pY-4 position has only a minor contribution and X represents amino acids not critical for the binding [23].
• This motif is found at tyrosine residue 800 in the beta2 subunit of the interleukin-12 receptor and is required for DNA binding and transcriptional activity of STAT4 [22].
• Decreased levels of STAT4 protein lead to decreased STAT4 DNA-binding activity and reduced proliferation and secretion of IFN-gamma [25].

Enzymatic interactions of STAT4

• Th2 T cells express only the IL-12R beta 1 and thus do not tyrosine phosphorylate STAT4 in response to IL-12 [1].
• Monocyte-expressed Stat4 in humans is phosphorylated in response to IFN-alpha, but not IL-12 [26].

Regulatory relationships of STAT4

• Thus, STAT4 activation was not IL-12 specific, and IL-12 and IFN-alpha activated STAT4 through both tyrosine and serine phosphorylation [19].
• IL-2 induces STAT4 activation in primary NK cells and NK cell lines, but not in T cells [17].
• Furthermore, gel shift analysis showed that TGF-beta1 did not prevent activated STAT4 and STAT5A from binding to DNA [27].
• These findings demonstrate that the activation of STAT4 alone is not sufficient for IL-12-induced IFN-gamma production and proliferation and suggest that other STATs play a role in these responses to IL-12 [28].
• An examination of cytokine signaling revealed that STAT4 and extracellular regulated kinase 1 (ERK1) activation by IL-12 was intact, whereas the activation of STAT1, -3, and -5 by IL-12 was lost [28].

Other interactions of STAT4

• Specific covalent cross-linking of nonactivated signal transducer and activator of transcription (STAT)-3, and to a lesser extent of STAT1 and STAT4, correlated with PDT dose [29].
• By contrast, STAT4 phosphorylation (and to some extent STAT3 activation) was independent from IL-28R/LICR2 tyrosine residues [15].
• Taken together, these observations extend the functional similarities between IFN-lambdas and type I IFNs and shed some new light on the mechanisms of activation of STAT2 and STAT4 by these cytokines [15].
• In ex vivo organ cultures of H. pylori-infected biopsies, neutralization of endogenous IL-12 down-regulated the expression of phosphorylated STAT4 and T-bet and reduced IFN-gamma production [30].
• The levels of signal transducer and activator of transcription 4 (STAT4), STAT6, and T-box expressed in T cells (T-bet) in total proteins extracted from gastric biopsies were determined by Western blotting [30].

Analytical, diagnostic and therapeutic context of STAT4

• In the present study, we demonstrated constitutive activation of STAT4 in HTLV-I-transformed T-cell lines MT-2, MT-4 and HUT102 by immunoprecipitation, Western blotting and electrophoretic mobility shift assay (EMSA) [2].
• The human STAT4 cDNA was cloned, and both STAT4 and STAT1 genes were mapped to human chromosome bands 2q32.2-->q32.3 by fluorescence in situ hybridization [18].
• These results indicate that defective IFN-gamma production is due to an intrinsic deficiency in STAT4 expression by posttransplantation patient lymphocytes and suggest strategies for circumventing this deficiency in cancer immunotherapy [4].
• By confocal microscopy, antibodies to TYK 2 reacted with the sperm tail as well as the apical region of sperm head, whereas antibodies to STAT 1 and STAT 4 reacted with the apical region of the sperm head [31].
• Cardiac allografts from C57BL/6 mice were transplanted into normal wild-type (WT), STAT4(-/-), and STAT6(-/-) BALB/c recipients [32].

References