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Results for “STAT4 Transcription Factor”

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PubMed1997

The mouse transcription factor Stat4 is expressed in haploid male germ cells and is present in the perinuclear theca of spermatozoa.

STAT (signal transducer and activator of transcription) proteins have been shown to be essential transcription factors which mediate biological effects of cytokines. Although most of the STATs have been shown to be widely expressed, Stat4 mRNA has been detected in only a few tissues, including the testis. In the present study, immunoblot analysis confirmed that the presence of Stat4 protein was similarly restricted, with the highest level observed in testis. In situ hybridization, immunoblot, and immunohistochemistry analyses revealed that in the testis, Stat4 was abundantly and exclusively expressed in male germ cells which have completed meiosis, at the round and elongating spermatid stages. Cytolocalization at various times of spermatid differentiation showed that the level of Stat4 protein increased in parallel in both cytoplasm and nuclei. No specific nuclear translocation that would have been an indicator of Stat4 activation was observed at any stage of spermatogenic differentiation. Interestingly, the Stat4 transcription factor was localized to the condensing perinuclear theca of spermatids, a localization that was confirmed by selective biochemical extraction of thecal proteins. Since the theca is known to depolymerize in the cytoplasm of the oocyte during the hours following fertilization, we hypothesized that sperm Stat4 would represent an original paternal contribution to the fertilized egg which may be involved in the onset of zygotic transcription.

Age Factors↗
PubMed2000

Attenuated cardiac allograft vasculopathy in mice with targeted deletion of the transcription factor STAT4.

BACKGROUND: To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients in our mouse cardiac transplant model of chronic rejection. METHODS AND RESULTS: At day 55 after transplantation, cardiac grafts placed into STAT4 -/- (n=10) had reduced frequency (24+/-2%) and severity (9+/-4%) of vascular occlusion compared with wild-type controls (n=7, frequency 70+/-12% [P<0.001], severity 25+/-6% [P<0.05]). This decrease was associated with reduced intragraft expression ((32)P RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon-gamma (P<0.001) and interleukin (IL)-2 (P<0.001). Furthermore, cardiac grafts in STAT4 -/- had fewer infiltrating CD45(+) mononuclear cells (99+/-27 cells/mm(3) compared with 551+/-168 cells/mm(3) in wild-type controls [P<0.05]) and reduced expression of P-selectin (P<0.001) and E-selectin (P<0.01) ligand, recently shown to regulate Th1 cell recruitment. In contrast, in grafts placed into STAT6 -/- (n=11), the development of cardiac allograft vasculopathy (frequency 62+/-8%, severity 28+/-6%) and Th2 cytokine profiles (IL-4, IL-10) were comparable to those in wild-type controls. CONCLUSIONS: Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1-specific lymphocyte recruitment, activation, and effector functions.

Animals↗
PubMed2000

IL-12 responsiveness and expression of IL-12 receptor in human peripheral blood monocyte-derived dendritic cells.

We analyzed the expression of IL-12Rbeta1 and IL-12Rbeta2 and the role of IL-12 in the activation of monocyte-derived dendritic cells (DCs) via IL-12Rbeta1-mediated signaling events. Flow cytometric analysis revealed that IL-12Rbeta1 was expressed in T cells, Con A blasts, and monocyte-derived DCs, but not in monocytes, while its transcript was detected in all of these cell types. Transcriptional expression of IL-12Rbeta2 was observed in T cells, Con A blasts, and monocyte-derived DCs, but not monocytes. The ligation of DCs as well as Con A blasts by IL-12 induced the production of GM-CSF, IL-1beta, IL-6, TNF-alpha, and IFN-gamma at the transcription levels. Furthermore, stimulation of DCs with IL-12 induced IL-12p40 transcript, but not IL-12p35 transcript, whereas this stimulation caused the expressions of both transcripts in Con A blasts. Stimulation of DCs with IL-12 caused a tyrosine phosphorylation of several intracellular proteins, and the pattern of these events were distinct from those of IL-12-stimulated Con A blasts. IL-12 also induced tyrosine phosphorylation of IL-12Rbeta1 as well as recruitment of several tyrosine-phosphorylated proteins to IL-12Rbeta1 in DCs and Con A blasts. Receptor engagement of DCs as well as Con A blasts by IL-12 resulted in activation of Janus kinase 2 and Tyk2 kinases and Stat3 and Stat4 transcription factors and the association of these proteins to IL-12Rbeta1. Stimulation with IL-12 caused a tyrosine phosphorylation and enzymatic activity of a family of mitogen-activated protein kinases, p38mapk. These results suggest that IL-12 acts directly on DCs to induce their functional activation via IL-12Rbeta1-mediated signaling events.

Cells, Cultured↗
PubMed2002

Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.

Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated inflammatory demyelinating autoimmune disease of the CNS that serves as an animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine that plays a crucial role in the induction of neural Ag-specific Th1 differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin (1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. In this study we have examined the effect and mechanism of action of curcumin on the pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice with curcumin significantly reduced the duration and clinical severity of active immunization and adoptive transfer EAE. Curcumin inhibited EAE in association with a decrease in IL-12 production from macrophage/microglial cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment of activated T cells with curcumin inhibited IL-12-induced tyrosine phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4 transcription factors. The inhibition of Janus kinase-STAT pathway by curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1 differentiation. These findings highlight the fact that curcumin inhibits EAE by blocking IL-12 signaling in T cells and suggest its use in the treatment of MS and other Th1 cell-mediated inflammatory diseases.

Adoptive Transfer↗
PubMed2000

Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity.

Interleukin-12 (IL-12) is a key immunoregulatory cytokine that promotes Th1 differentiation and cell-mediated immune responses. The transcription factor STAT4 (signal transducer and activator of transcription 4) is an important element in mediating IL-12 signals, as evidenced by the fact that STAT4(-/-) mice display impaired responsiveness to IL-12 and deficient Th1 differentiation. STAT4 is inducibly phosphorylated on tyrosine and serine in response to IL-12, but the kinase(s) responsible for the latter event is unknown. Here we show that IL-12 induces STAT4 phosphorylation on serine 721 and that mutation of serine 721 interferes with STAT4 transcriptional activity. In addition, we show that mutation of tyrosine 693 abrogates IL-12-induced STAT4 tyrosine phosphorylation and transcriptional activity. Although the site surrounding serine 721 is an optimum consensus sequence for mitogen-activated family of protein kinases (MAPKs)-mediated phosphorylation, we demonstrate that IL-12 does not induce extracellular signal-regulated kinase (ERK) or c-Jun N-terminal kinase (JNK) activation in T and natural killer (NK) cells and that IL-12-induced STAT4 transcriptional activity is not affected by these kinases. Rather, we show that IL-12 induces p38 activation. Moreover, we demonstrate that p38alpha and its upstream activator, MKK6, phosphorylate STAT4 on serine 721, and are required for STAT4 full transcriptional activity induced by IL-12, establishing the MKK6/p38alpha/STAT4 pathway as an important mediator of IL-12 actions. (Blood. 2000;96:1844-1852)

3T3 Cells↗
PubMed2000

Regulation of c-myc transcription by interleukin-2 (IL-2). Identification of a novel IL-2 response element interacting with STAT-4.

Regulation of c-myc expression is known to occur at the level of transcription initiation. However, the participating promoter elements and their cognate binding proteins have not been fully characterized. c-myc transcription can be stimulated by a number of cytokines including interleukin-2 (IL-2). We have identified a novel IL-2-responsive element, located in the 5'-flanking region of the c-myc gene, between nucleotides -1406 and -1387 (relative to the P2 promoter). This element belongs to the family of interferon-gamma activation site-like responsive elements and has the core sequence TTCCAATAA. We confirmed that IL-2-mediated signaling involves activation by phosphorylation of Jak2 tyrosine kinase and subsequently STAT4. The transcription factor STAT4 binds the TTCCAATAA motif within this responsive element and, therefore, is probably involved in enhancing c-myc transcription upon IL-2 stimulation. Our results propose participation of Jak2 and STAT4 in IL-2-induced up-regulation of c-myc.

Binding Sites↗
PubMed2003

PIASx is a transcriptional co-repressor of signal transducer and activator of transcription 4.

In response to interleukin 12 (IL-12) stimulation, a latent cytoplasmic transcription factor, Stat4 (signal transducer and activator of transcription 4), becomes tyrosine-phosphorylated and translocates into the nucleus where it binds to DNA to activate transcription. Cofactors that can directly bind and regulate Stat4 activity have not been described. We report here that PIASx, a member of the protein inhibitor of activated STAT (PIAS) family, is a negative regulator of Stat4. PIASx becomes associated with Stat4 following IL-12 stimulation in vivo. PIASx inhibits IL-12-stimulated and Stat4-dependent gene activation in human T cells. PIASx does not inhibit the DNA binding activity of Stat4. Instead PIASx is present in the Stat4-DNA binding complex. Finally the inhibitory activity of PIASx on Stat4-mediated gene activation is abolished by the histone deacetylase inhibitor trichostatin A. Our results suggest that PIASx may function as a co-repressor of Stat4.

Animals↗
PubMed2002

IL-23: a cytokine that acts on memory T cells.

The newly discovered cytokine interleukin (IL)-23 shares some in vivo functions with IL-12, including the activation of the transcription factor STAT4 (signal tranducer and activator of transcription-4). Indeed, the receptors for each appear to share one subunit, but also have at least one distinct subunit. Frucht discusses the similarities of IL-12 and IL-23 and the effects that distinguish one from the other. In contrast to IL-12, IL-23 appears to participate in the proliferative signal in memory T cells. More functions that distinguish IL-23 from IL-12 are likely to be uncovered as soon as the other component(s) of the IL-23 receptor are molecularly cloned and characterized.

Animals↗
PubMed2006

T helper type 1-specific Brg1 recruitment and remodeling of nucleosomes positioned at the IFN-gamma promoter are Stat4 dependent.

Transcriptional competence of the interferon-gamma (IFN-gamma) locus is enhanced as Th1 effectors develop from naive CD4 T lymphocytes; conversely, this gene is repressed during Th2 differentiation. We now show that the Switch (Swi)-sucrose nonfermenter (SNF) component Brahma-related gene 1 (Brg1) is recruited, and positioned nucleosomes are remodeled, in a Th1-specific manner that is dependent on the transcription factor Stat4 and calcineurin phosphatase activity. Interference with specific components of mammalian Swi-SNF complexes decreased CD4 T cell differentiation into IFN-gamma-positive Th1 cells. These findings reveal a collaborative mechanism of IFN-gamma gene regulation during Th1 differentiation and suggest that a Th1-specific chromatin structure is created by early recruitment of Swi-SNF complexes and nucleosome remodeling dependent on Stat4 and calcineurin activation.

Animals↗
PubMed2001

Stat transcription factors in mammary gland development and tumorigenesis.

Two members of the Stat family of transcription factors play a vital role in mouse mammary gland development. Stat5a was originally described as a regulator of milk protein gene expression and was subsequently shown to be essential for mammary development and lactogenesis. In contrast, Stat3 is an essential mediator of apoptosis and post-lactational regression. Other members of the Stat family may have specific, but as yet undemonstrated, functions in mammary development. However, since Stat1 activity is regulated during mammary development in a pattern different from Stats 3 and 5, this factor too may have a functional role. Although both Stat4 and Stat6 are expressed in mammary tissue, it seems unlikely that they will have a significant function as each of these Stats is activated in response to a limited number of cytokines. Given the essential regulatory roles of Stat signaling molecules in mammary development, it was not surprising to discover that constitutively activated Stat factors are a feature of human breast cancers. Sustained Stat activity has also been described in a variety of tumors including leukemias. The cause of this sustained activation is not clear but probably involves mutation of one of the many Stat regulatory proteins or dysregulation of other signaling pathways which modulate Stat activity. It is now important to understand the mechanism of constitutive Stat activity and to develop strategies which will abrogate aberrant Stat signaling in tumors in vivo.

Animals↗
PubMed2002

Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection.

NK cell cytotoxicity, IFN-gamma expression, proliferation, and accumulation are rapidly induced after murine CMV infections. Under these conditions, the responses were shown to be elicited in overlapping populations. Nevertheless, there were distinct signaling molecule requirements for induction of functions within the subsets. IL-12/STAT4 was critical for NK cell IFN-gamma expression, whereas IFN-alphabeta/STAT1 were required for induction of cytotoxicity. The accumulation/survival of proliferating NK cells was STAT4-independent but required IFN-alphabeta/STAT1 induction of IL-15. Taken together, the results define the coordinated interactions between the cytokines IFN-alphabeta, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors' nonredundant functions under in vivo physiological conditions.

Animals↗
PubMed2006

Dendritic-cell maturation alters intracellular signaling networks, enabling differential effects of IFN-alpha/beta on antigen cross-presentation.

The broad and often contrasting effects of type I interferons (IFNs) in innate and adaptive immunity are belied by the signaling via a single receptor, IFN-alpha receptor (IFNAR). Here, we show that IFN-alpha/beta induces opposing effects on the immunologic outcome of antigen cross-presentation depending on dendritic cell (DC) maturation status. Despite equivalent IFNAR expression, immature conventional DCs (cDCs) activate 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. Importantly, STAT1 signaling resulted in significant inhibition of CD40L-induced IL-12 production, accounting for the inhibition of CD8+ T-cell activation. 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.

Animals↗
PubMed2003

IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells.

NK and T cell-derived IFN-gamma is a key cytokine that stimulates innate immune responses and directs adaptive T cell response toward Th1 type. IL-15, IL-18, and IL-21 have significant roles as activators of NK and T cell functions. We have previously shown that IL-15 and IL-21 induce the expression of IFN-gamma, T-bet, IL-12R beta 2, and IL-18R genes both in NK and T cells. Now we have studied the effect of IL-15, IL-18, and IL-21 on IFN-gamma gene expression in more detail in human NK and T cells. IL-15 clearly activated IFN-gamma mRNA expression and protein production in both cell types. IL-18 and IL-21 enhanced IL-15-induced IFN-gamma gene expression. IL-18 or IL-21 alone induced a modest expression of the IFN-gamma gene but a combination of IL-21 and IL-18 efficiently up-regulated IFN-gamma production. We also show that IL-15 activated the binding of STAT1, STAT3, STAT4, and STAT5 to the regulatory sites of the IFN-gamma gene. Similarly, IL-21 induced the binding of STAT1, STAT3, and STAT4 to these elements. IL-15- and IL-21-induced STAT1 and STAT4 activation was verified by immunoprecipitation with anti-phosphotyrosine Abs followed by Western blotting with anti-STAT1 and anti-STAT4 Abs. IL-18 was not able to induce the binding of STATs to IFN-gamma gene regulatory sites. 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.

Adjuvants, Immunologic↗
PubMed2000

Cutting edge: Chandra, a novel four-transmembrane domain protein differentially expressed in helper type 1 lymphocytes.

Development of naive Th cells into Th1 and Th2 effector populations requires coordinated expression of a complex set of genes. In this study, we have identified a novel four-transmembrane domain protein, Chandra, that is differentially expressed in Th1 cells. Chandra expression is observed in STAT4- and IFN-gamma-deficient mice, indicating that Chandra is not an IL-12- or IFN-gamma-responsive gene. Interestingly, Chandra mRNA is detected in anti-CD3-activated T cells from STAT6-deficient mice in the absence of any differentiation conditions. Furthermore, neutralization of IL-4 signaling is sufficient to induce transcription of Chandra in anti-CD3-activated T cells from wild-type mice, demonstrating that STAT6 signaling is required to repress Chandra expression in activated T cells and Th2 subsets. This is the first demonstration of a differentially expressed four-transmembrane domain protein in Th1 cells.

Amino Acid Sequence↗
PubMed2004

Interleukin-12-induced interferon-gamma production by human peripheral blood T cells is regulated by mammalian target of rapamycin (mTOR).

Depending on the type of external signals, T cells can initiate multiple intracellular signaling pathways that can be broadly classified into two groups based on their sensitivity to the immunosuppressive drug cyclosporin A (CsA). Interleukin (IL)-12-mediated interferon (IFN)-gamma production by activated T cells has been shown to be CsA-insensitive. In this report, we demonstrate that the IL-12-induced CsA-resistant pathway of IFN-gamma production is sensitive to rapamycin. Rapamycin treatment resulted in the aberrant recruitment of Stat3, Stat4, and phospho-c-Jun to the genomic promoter region resulting in decreased IFN-gamma transcription. IL-12-induced phosphorylation of Stat3 on Ser-727 was affected by rapamycin, which may be due to the effect of rapamycin on the IL-12-induced interaction between mammalian target of rapamycin (mTOR) and Stat3. In accordance with this, reduction in the mTOR protein level by small interfering RNA resulted in suppression of Stat3 phosphorylation and decreased production of IFN-gamma after IL-12 stimulation. These results suggest that mTOR may play a major role in IL-12-induced IFN-gamma production by activated T cells.

CD28 Antigens↗
PubMed2002

Critical role for STAT4 activation by type 1 interferons in the interferon-gamma response to viral infection.

Interferons (IFNs) are essential for host defense. Although the antiviral effects of the type 1 IFNs IFN-alpha and IFN-beta (IFN-alpha/beta) have been established, their immunoregulatory functions, especially their ability to regulate IFN-gamma production, are poorly understood. 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 production during viral infections of mice, in concert with T cell receptor-derived signals. In contrast, STAT1 appears to negatively regulate IFN-alpha/beta induction of IFN-gamma. 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.

Animals↗
PubMed2005

Suppression of hepatocellular carcinoma by transplantation of ex-vivo immune-modulated NKT lymphocytes.

NKT cells are a regulatory subset of T lymphocytes with immune modulatory effects and an important role in anti-tumor immunity. The feasibility of "ex-vivo education" of NKT cells has recently been demonstrated. To evaluate the anti-tumor effect of ex-vivo immune-modulated NKT lymphocytes in a murine model of hepatocellular carcinoma. Athymic Balb/C mice were sublethally irradiated and transplanted with human Hep3B HCC. NKT cells prepared from immunocompetent Balb/C mice were pulsed ex vivo with HCC-derived antigens (Group A), Hep3B cells (group B) or BSA (group C), and adoptively transferred into HCC harboring mice (1 x 0(6) NKT cells per mouse). Group D mice did not undergo NKT cell transplantation. Group E mice were transplanted with 1 x 10(6) NKT cells from HBV-immunized donors. Mice were followed for tumor size and weight. To determine the mechanism of the anti-tumor effect, intrasplenic lymphocyte populations were analyzed by FACS for NKT, CD4+ and CD8+ lymphocyte subpopulations; STAT 1, 4 and 6 expression in splenocytes was assessed by Western blot, and serum cytokine levels were measured by ELISA. Adoptive transfer of NKT cells pulsed with HCC-derived antigens (group A) and NKT cells from immunized donors (group E) resulted in complete disappearance of tumors within 4 weeks and attenuated weight loss (6.5% and 7% in groups A and E, respectively). In contrast, mice in groups B, C, and D developed large, necrotic tumors and severe weight loss (21%, 17% and 23% weight loss in groups B, C, and D, respectively). NKT/CD4 and CD8/CD4 ratios were significantly increased in groups A and E (12.3 and 17.6 in groups A and D, respectively, compared to 6.4, 4.8 and 5.6 in groups B, C and D, respectively, for the NKT/CD4 ratio; 41 and 19.8 in groups A and E, respectively, compared to 6.5, 11.8 and 3.2 in groups B, C, and D, respectively, for the CD8/CD4 ratio). Expression of the transcription factor STAT4 was evident in group A, but not in groups B-D. Serum IFNgamma, IL12 and IL4 levels were increased in groups A and E. Adoptive transfer of NKT lymphocytes exposed ex vivo by HCC-derived antigens loaded on dendritic cells and NKT cells from immunized donors led to suppression of HCC in mice. NKT-mediated anti-tumor activity was associated increased NKT and CD8+ T lymphocyte numbers, increased expression of STAT4, a marker for IL-12 activity and elevated serum levels of the proinflammatory cytokines IFNgamma and IL12, and of IL4. Ex-vivo modulation of NKT lymphocytes holds promise as a novel mode of immune therapy for HCC.

Adoptive Transfer↗
PubMed2003

The oncogenic fusion protein-tyrosine kinase ZNF198/fibroblast growth factor receptor-1 has signaling function comparable with interleukin-6 cytokine receptors.

The reciprocal t(8;13) chromosome translocation results in a fusion gene (FUS) in which the N-terminal half of the zinc finger protein ZNF198 is combined with the cytoplasmic domain of the fibroblast growth factor receptor-1 (FGFR1). Expression of FUS is suggested to provide growth-promoting activity to myeloid cells similar to the activity of hematopoietic cytokine receptors. This study determined the specificity of FUS to activate signal transduction pathways. Because no tumor cell line expressing FUS was available, the mode of FUS action was identified in cells transiently and stably transfected with an expression vector for FUS. FUS acted as a constitutively active protein-tyrosine kinase and mediated phosphorylation of STAT1, 3, and 5 but not STAT4 and 6. The same specificity but lower activity was determined for normal FGFR1. STAT activation by FUS, similar to that by interleukin-6-type cytokines, promoted STAT-specific induction of genes. The functionality of FUS, as well as the relative recruitment of STAT isoforms, was determined by the dimerizing function of the zinc finger domain. Replacement of the ZNF198 portion by the Bcr portion as present in the t(8;22) translocation shifted the signaling toward a more prominent STAT5 activation. This study documents that both gene partners forming the fusion oncogene define the activity and the signaling specificity of the protein-tyrosine kinase of FGFR1.

Animals↗