Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IL-27 is a novel IL-12 family member that plays a role in the early regulation of Th1 initiation, induces proliferation of naive CD4+ T cells, and synergizes with IL-12 in IFN-gamma production. It has been recently reported that IL-27 induces T-bet and IL-12Rbeta2 expression through JAK1/STAT1 activation. In the present study, we further investigated the JAK/STAT signaling molecules activated by IL-27 and also the role of STAT1 in IL-27-mediated responses using STAT1-deficient mice. In addition to JAK1 and STAT1, IL-27-activated JAK2, tyrosine kinase-2, and STAT2, -3, and -5 in naive CD4+ T cells. The activation of STAT2 and STAT5, but not of STAT3, was greatly diminished in STAT1-deficient naive CD4+ T cells. Comparable proliferative response to IL-27 was observed between STAT1-deficient and wild-type naive CD4+ T cells. In contrast, IL-27 hardly induced T-bet and subsequent IL-12Rbeta2 expression, and synergistic IFN-gamma production by IL-27 and IL-12 was impaired in STAT1-deficient naive CD4+ T cells. Moreover, IL-27 augmented the expression of MHC class I on naive CD4+ T cells in a STAT1-dependent manner. These results suggest that IL-27 activates JAK1 and -2, tyrosine kinase-2, STAT1, -2, -3, and -5 in naive CD4+ T cells and that STAT1 plays an indispensable role in IL-27-induced T-bet and subsequent IL-12Rbeta2 expression and MHC class I expression as well but not proliferation, while STAT3 presumably plays an important role in IL-27-induced proliferation.
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PMID:An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells. 1535 35

The development of acute pancreatitis (AP) is triggered by acinar events, but the subsequent extra-acinar events, particularly a distinct immune response, appear to determine its severity. Cytokines modulate this immune response and are derived not only from immunocytes but also from pancreatic acinar cells. We studied whether pancreatic acinar cells were also capable of responding to cytokines. The JAK/STAT-pathway represents the main effector for many cytokines. Therefore, expression and regulation of JAK and STAT proteins were investigated in rat pancreatic acinar cells. Western blotting showed expression of JAK1, JAK2, Tyk2, and STAT1, STAT2, STAT3, STAT5, STAT6. In addition, STAT1 was reversibly tyrosine-phosphorylated upon the procedure of acinar cell isolation. In contrast, STAT3-phosphorylation occurred spontaneously after pancreas removal and was not reversible within 8 h. STAT1 phosphorylation was also observed upon treatment with IFN-gamma but not upon EGF, TNF-alpha or IL-6, and inhibited by the JAK2-inhibitor AG-490. Immunohistochemistry revealed cytoplasmic expression of unphosphorylated STAT1 in untreated acinar cells and nuclear translocation of phosphorylated STAT1 following IFN-gamma-treatment. Interestingly, although CCK leads to the activation of multiple stress pathways in pancreatic acinar cells, we found no influence of CCK on phosphorylation of STAT1, STAT3, or STAT5 in the pancreas. In conclusion, our data provide further evidence that pancreatic acinar cells are able to interact with immune cells. Besides stimulating immune cells via cytokine secretion, acinar cells are in turn capable of responding to IFN-gamma via JAK2 and STAT1 which may have an impact on the development of AP.
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PMID:JAK and STAT proteins are expressed and activated by IFN-gamma in rat pancreatic acinar cells. 1549 10

Rac1 GTPase is implicated as a signaling mediator in various cellular events. In this study, we show that Rac1 contributes to IFN-gamma-induced inflammatory responses in rat astrocytes. We revealed that IFN-gamma rapidly stimulated activation of Rac1 in C6 astroglioma cells by investigating GST-PAK-PBD-binding ability. We also found that Rac1 deficiency led to attenuation of IFN-gamma-responsive transcriptional responses. Compared with levels in control cells, IFN-gamma-induced IFN-gamma-activated sequence promoter activity was markedly reduced in both C6 astroglioma cells and primary astrocytes expressing RacN17, a well-characterized Rac1-negative mutant. The expression of several IFN-gamma-responsive genes, such as MCP-1 and ICAM-1, was also reduced in cells expressing RacN17. Consistent with these observations, IFN-gamma-induced phosphorylation of STAT1 and STAT3 was lower in C6 cells expressing RacN17 (referred to as C6-RacN17) than in control cells. However, there was no difference in expression level of IFN-gammaRalpha subunit and IFN-gamma-induced phosphorylation of JAK1 between C6 control and C6-RacN17 cells. Interestingly, Rac1 appeared to associate with IFN-gammaRalpha and augment the interaction of IFN-gammaR with either STAT1 or STAT3 in response to IFN-gamma. Taken together, we suggest that Rac1 may serve as an auxiliary mediator of IFN-gamma-signaling, at least at the level of STAT activation, thus contributing to maximal activation of IFN-gamma-responsive inflammatory signaling in rat astrocytes.
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PMID:Rac1 contributes to maximal activation of STAT1 and STAT3 in IFN-gamma-stimulated rat astrocytes. 1549 21

The effects of falcarindiol on the expression of inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide/interferon-gamma (LPS/IFN-gamma) in rat primary astrocytes were investigated. The molecular mechanisms underlying falcarindiol that confers its effect on iNOS expression were also elucidated. Falcarindiol abrogated the LPS/IFN-gamma-mediated induction of iNOS by about 80%. Falcarindiol attenuated the induction of iNOS in a concentration-dependent manner. The inhibitory effect of falcarindiol on iNOS induction was attributable to decrease in the protein content and the mRNA level of iNOS. Treatment with 50 microM of falcarindiol for 30 min decreased LPS/IFN-gamma-induced nuclear factor-kappaB (NF-kappaB) activation by 32%. Treatment with 50 microM of falcarindiol for 60 min diminished the LPS/IFN-gamma-mediated activation of IkappaB kinase-alpha (IKK-alpha) and IKK-beta by 28.2 and 29.7%, respectively. Falcarindiol modulated the nuclear translocation of signal transducer and activator of transcription 1 (Stat1) in a time-dependent manner. Falcarindiol (50 microM) decreased the tyrosine phosphorylation of janus kinase 1 (JAK1) by 84.8% at 5 min. Falcarindiol also abrogated the tyrosine phoshorylation of JAK2 by 82.3% at 10 min.The present study demonstrates that falcarindiol attenuated the activation of IKK and JAK contributing to the blockade of activation of NF-kappaB and Stat1, thereby leading to the suppression of iNOS expression.
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PMID:Falcarindiol impairs the expression of inducible nitric oxide synthase by abrogating the activation of IKK and JAK in rat primary astrocytes. 1564 67

Effector functions mediated by NK cells involve cytotoxicity and transcription-dependent production and release of cytokines and chemokines. Although the JAK/STAT pathway mediates lymphokine-induced transcriptional regulation in NK cells, very little is known about transcriptional regulation induced during cell-cell contact. We demonstrate that the Wiskott-Aldrich syndrome protein (WASp) is an important component for integration of signals leading to nuclear translocation of NFAT2 and NF-kappaB (RelA) during cell-cell contact and NKp46-dependent signaling. This WASp function is independent of its known role in F-actin polymerization and cytoskeletal rearrangement. Absence of WASp results in decreased accumulation of calcineurin, WASp-interacting protein, and molecules upstream of calcium mobilization, i.e., activated ZAP70 and phospholipase C-gamma1, in the disorganized NK cell immune synapse. Production of GM-CSF, but not IFN-gamma, is decreased, while natural cytotoxicity of Wiskott-Aldrich syndrome-NK cells is maintained. Our results indicate that WASp independently regulates its dual functions, i.e., actin cytoskeletal remodeling and transcription in NK cells.
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PMID:The Wiskott-Aldrich syndrome protein regulates nuclear translocation of NFAT2 and NF-kappa B (RelA) independently of its role in filamentous actin polymerization and actin cytoskeletal rearrangement. 1572 66

Human beta-defensins are antimicrobial peptides produced by epithelial cells. To date, 28 beta-defensins have been described and the expression of a select few has been classified as constitutive or inducible. Most studies have evaluated expression and regulation using a limited number of primary cell cultures or immortalized cell lines. The goal of this study was to quantitatively assess the in vitro expression and inducibility profiles of human beta-defensins, HBD-1, HBD-2, and HBD-3 across a number of primary gingival keratinocyte cultures. Cultured cells from 14 human subjects were stimulated with interleukin-1 beta (IL-1beta), IL-2, IL-6, IL-8, IL-12, tumor necrosis factor alpha (TNF-alpha), gamma interferon (IFN-gamma) or Escherichia coli lipopolysaccharide (LPS) and analyzed by reverse transcription (RT)-PCR. A subset of cultures were quantitatively assessed by real-time PCR. HBD-1 presented the highest and most heterogeneous expression at the basal level (non-stimulated) as compared to expression of HBD-2 and HBD-3, which was significantly lower and homogeneous. IFN-gamma was a primary inducer for HBD-1 and HBD-3, while IL-1beta and TNF-alpha were primary inducers for HBD-2. Sporadic induction was seen for IL-2, IL-6 and LPS. Synergistic expression was seen when various cytokines were combined. Interestingly, the induction potential of each beta-defensin was directly correlated to its basal expression. An inhibitor of JAK2 kinase (Janus kinase), down-regulated IFN-gamma-induced HBD-1 and HBD-3 expression, suggesting a role for the JAK/signal transducer and activator of transcription (STAT) signaling pathway in their expression. HBD-2 protein expression of supernatants and cell lysates paralleled mRNA expression. The results suggest that beta-defensin expression and induction in gingival keratinocytes is similar to that seen in other tissue. However, the novel finding of considerable variation among induction levels and the correlation of the induction with basal expression suggests that these innate response elements may play a key role in susceptibility or resistance to disease in the oral cavity.
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PMID:Correlation between beta-defensin expression and induction profiles in gingival keratinocytes. 1582 97

We reported previously that 23% of human lung adenocarcinoma cell lines were unresponsive to IFN-gamma. To extend this finding to cancer cells derived from distinct tissues of origin, we assessed IFN-gamma receptor signaling in the LNCaP human prostate adenocarcinoma cell line, which in previous experiments by others failed to induce a range of IFN-dependent biological responses. In this report, we show that LNCaP cells fail to respond to either IFN-gamma or IFN-alpha because of an impairment in the proximal signaling events downstream of both IFN-gamma and IFN-alpha/beta receptors that lead to the activation of STAT1. Furthermore, we show that LNCaP insensitivity to the IFNs is a result of the absence of expression of the JAK1 kinase, an obligate component shared by both IFN-gamma and IFN-alpha/beta receptors. JAK1 was undetectable in LNCaP cells at both protein and message levels. Treatment of LNCaP cells with a combination of inhibitors of DNA methyltransferases and histone deacetylases induced expression of JAK1 message. These results identify the molecular basis for IFN insensitivity in the LNCaP cell line and suggest that epigenetic silencing of key immunologic signaling components may be one mechanism by which tumor cells evade immune detection and elimination.
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PMID:IFN unresponsiveness in LNCaP cells due to the lack of JAK1 gene expression. 1583 80

We have recently demonstrated that granulocyte-colony stimulating factor (G-CSF) delays human neutrophil apoptosis via up-regulation of cellular inhibitor of apoptosis 2 (cIAP2), which is dependent on activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Here, we show that type I and type II interferons (IFNs), which bind to the distinct receptors, exert the antiapoptotic effect on human neutrophils through the similar mechanism. IFN-alpha (type I IFN) and IFN-gamma (type II IFN), like G-CSF, delayed human neutrophil apoptosis through the protein synthesis-dependent mechanism. Stimulation of neutrophils with IFN-alpha or IFN-gamma resulted in tyrosine phosphorylation of STAT1 and STAT3 but not phosphorylation of STAT5, Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. IFN-alpha and IFN-gamma induced the expression of transcripts of cIAP2 and suppressor of cytokine signaling 1 and 3, but not cIAP1, Mcl-1, and A1. IFN-alpha- and IFN-gamma-induced up-regulation of cIAP2 mRNA and protein, phosphorylation of STAT3, and antiapoptotic effect were inhibited significantly by pretreatment of cells with AG490, a specific inhibitor of JAK2. These findings suggest that cIAP2 expression is up-regulated by IFN-alpha and IFN-gamma through, at least in part, activation of the JAK2-STAT3 pathway, and increased expression of the cIAP2 protein may contribute to an IFN-alpha- and IFN-gamma-mediated antiapoptotic effect on human neutrophils.
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PMID:Type I and type II interferons delay human neutrophil apoptosis via activation of STAT3 and up-regulation of cellular inhibitor of apoptosis 2. 1584 43

Immunostimulatory CpG motifs can preferentially induce Th1 immune responses and have been applied to treat Th2-dominant disease. In this study, we investigated whether a plasmid with the addition of 20 copies of an immunostimulatory CpG motif (pB-CpG20) might prevent the development of scleroderma-like syndrome in tight-skin (Tsk/+) mice. Administration of pB-CpG20 to Tsk/+mice every 3 weeks starting at the age of 1 week reduced skin thickness and collagen content compared to that of pB or saline. The reduction was long lasting even after halting the treatment. Furthermore, this treatment partially reduced the production of anti-nuclear antibodies although it did not decrease the incidence of lung emphysema. pB-CpG20 increased the number of spleen cells secreting IFN-gamma and reduced that of the cells secreting IL-4 in vivo and in vitro compared to saline. These results suggest that repeated administration of a CpG-enriched plasmid can ameliorate scleroderma-like syndrome by biasing Th1 immunity in young Tsk/+mice.
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PMID:Therapeutic effect of CpG-enriched plasmid administration on the tight-skin mouse model of scleroderma. 1584 40

The transcription factor T-bet promotes the differentiation of inflammatory Th1 T helper cells. T-bet expression in lymphoid cells is regulated by cytoplasmic signaling through Janus kinase phosphorylation, nuclear signaling using signal transducers and activators of transcription (Stat) family proteins, and autocrine/paracrine feedback involving interferon (IFN)-gamma. T-bet is here shown to be present in epithelial cells of the human female reproductive tract. Regulation of T-bet expression was modulated by cytokines and the female reproductive steroids, estrogen, and progesterone. The mechanisms of T-bet regulation in epithelia differ from those in conventional immune cells. During a 15-d exposure to progesterone, T-bet levels in endometrial epithelial cells (EECs) undulated. Prior exposure to estrogen enhanced these effects. More prolonged exposure of EECs to these hormones, singly or in combination, suppressed T-bet production. Stat1 and Stat5 bound to the EEC T-bet regulatory region (TRR) at the IFN-gamma-activated sequence site, but Stat3 and Stat4 did not. Binding of Stat1 and Stat5 to the TRR were modified by progesterone in distinct ways. Estrogen suppressed the binding of Stat1 and Stat5 to the TRR. Mutation of gamma-activated sequence element reduced T-bet promoter activity, binding of Stat proteins to the TRR and regulation of the promoter by cytokines and hormones. In EECs, cytokine exposure caused phosphorylation of Janus kinase 2 and TRR-bound Stat proteins; female steroid hormones altered only phosphorylation of TRR-bound Stat5. Although there is no autocrine IFN-gamma feedback loop in reproductive tract epithelial cells, an IL-15/T-bet positive feedback loop may exist. The implications of hormonally regulated T-bet expression are discussed.
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PMID:Female steroid hormones use signal transducers and activators of transcription protein-mediated pathways to modulate the expression of T-bet in epithelial cells: a mechanism for local immune regulation in the human reproductive tract. 1586 May 46


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