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)

Mucus hypersecretion and persistent airway inflammation are common features of various airway diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. One key question is: does the associated airway inflammation in these diseases affect mucus production? If so, what is the underlying mechanism? It appears that increased mucus secretion results from increased mucin gene expression and is also frequently accompanied by an increased number of mucous cells (goblet cell hyperplasia/metaplasia) in the airway epithelium. Many studies on mucin gene expression have been directed toward Th2 cytokines such as interleukin (IL)-4, IL-9, and IL-13 because of their known pathophysiological role in allergic airway diseases such as asthma. However, the effect of these cytokines has not been definitely linked to their direct interaction with airway epithelial cells. In our study, we treated highly differentiated cultures of primary human tracheobronchial epithelial (TBE) cells with a panel of cytokines (interleukin-1alpha, 1beta, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, and tumor necrosis factor alpha). We found that IL-6 and IL-17 could stimulate the mucin genes, MUC5B and MUC5AC. The Th2 cytokines IL-4, IL-9, and IL-13 did not stimulate MUC5AC or MUC5B in our experiments. A similar stimulation of MUC5B/Muc5b expression by IL-6 and IL-17 was demonstrated in primary monkey and mouse TBE cells. Further investigation of MUC5B expression demonstrated that IL-17's effect is at least partly mediated through IL-6 by a JAK2-dependent autocrine/paracrine loop. Finally, evidence is presented to show that both IL-6 and IL-17 mediate MUC5B expression through the ERK signaling pathway.
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PMID:Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop. 1262 14

Through DNA microarray analysis and quantitative PCR verification, we have identified additional IL-17A-inducible genes-IL-19, CXCL-1, -2, -3, -5, and -6-in well-differentiated normal human bronchial epithelial cells. These genes, similar to previously described human beta-defensin-2 (HBD-2) and CCL-20, were induced by a basolateral treatment of IL-17A, and regulated by PI3K signaling and NF-kappaB activation. For PI3K signaling, increases of cellular PIP(3) and phosphorylation of downstream molecules, such as Akt and glycogen synthase kinase-3beta (GSK3beta) (S9), were detected. Induced gene expression and HBD-2 promoter activity were attenuated by LY294002, p110alpha small-interfering RNA (siRNA), as well as by an overexpression of constitutively active GSK3beta(S9A) or wild-type phosphatase and tensin homolog. Increased phosphorylation of JAK1/2 after IL-17A treatment was detected in primary normal human bronchial epithelium cells. Transfected siRNAs of JAK molecules and JAK inhibitor I decreased IL-17A-induced gene expression and GSK3beta(S9) phosphorylation. However, both JAK inhibitor I and PI3K inhibitor had no effect on the DNA-binding activities of p65 and p50 to NF-kappaB consensus sequences. This result suggested a JAK-associated PI3K signaling axis is independent from NF-kappaB activation. With siRNA to knockdown STIR (similar expression to fibroblast growth factor and IL-17R; Toll-IL-1R)-related signaling molecules, such as Act1, TNFR-associated factor 6 (TRAF6), and TGF-beta-activated kinase 1 (TAK1), and transfection of A52R, an inhibitor of the MyD88/TRAF6 complex, or dominant-negative TAK1, IL-17A-inducible gene expression and HBD-2 promoter activity were reduced. Additionally, IL-17A-induced p65 and p50 NF-kappaB activations were confirmed and their nuclear translocations were down-regulated by siRNAs of TRAF6 and TAK1. These results suggest that two independent and indispensable signaling pathways-1) JAK1-associated PI3K signaling and 2) Act1/TRAF6/TAK1-mediated NF-kappaB activation-are stimulated by IL-17A to regulate gene induction in human airway epithelial cells.
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PMID:Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-kappaB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells. 1798 39

Interleukin (IL)-17 is a pro-inflammatory cytokine produced by recently described T helper type 17 (Th17) cells, which have critical role in immunity to extracellular bacteria and the pathogenesis of several autoimmune disorders. IL-6 and transforming growth factor (TGF)-beta are crucial for the generation of Th17 cells in mice, while the production of IL-17 is supported by various cytokines, including IL-23, IL-1beta, IL-21, IL-15 and tumour necrosis factor (TNF)-alpha. In this study, the influence of a multifunctional cytokine, macrophage migration inhibitory factor (MIF), on IL-17 production in mice was investigated. Treatment of lymph node cells (LNCs) with recombinant MIF up-regulated mitogen-stimulated IL-17 expression and secretion. Additionally, LNCs from MIF knockout mice (mif(-/-)) had severely impaired production of IL-17, as well as of IL-1beta, IL-6, IL-23 and TGF-beta. When stimulated with recombinant IL-1beta, IL-23 or TNF-alpha, mitogen-triggered mif(-/-) LNCs were fully able to achieve the IL-17 production seen in wild-type (WT) LNCs, while the addition of IL-6 and TGF-beta had no effect. Finally, after injection of mice with complete Freund's adjuvant, secretion of IL-17 as well as the number of IL-17-positive cells was significantly lower in the draining lymph nodes of mif(-/-) mice in comparison with WT mice. The effect of MIF on IL-17 production was dependent on p38, extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and Janus kinase 2/signal transducer and activator of transcription 3 (Jak2/STAT3), and not on nuclear factor (NF)-kappaB and nuclear factor of activated T cells (NFAT) signalling. Bearing in mind the contribution of MIF and IL-17 to the pathology of inflammatory and autoimmune disorders, from the results presented here it seems plausible that targeting MIF biological activity could be a valid therapeutic approach for the treatment of such diseases.
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PMID:Macrophage migration inhibitory factor stimulates interleukin-17 expression and production in lymph node cells. 1862 29

Purified protein derivative (PPD) or tuberculin skin testing is used to identify infected individuals with Mycobacterium tuberculosis (Mtb) and to assess cell-mediated immunity to Mtb. In the present study, we compared PBMC cultures in the presence of tuberculin or Candida antigens using cytokine bead arrays and RNA microarrays. Measurements of different cytokines and chemokines in supernatants of PMBC cultures in the presence of PPD showed increased levels of interferon (IFN)-gamma in active tuberculosis infection (ATBI) and latent TB infected (LTBI) compared to controls, and increased levels of TNF-alpha in ATBI compared with LTBI. Also, we found increase of IL-6 in cultures of PPD positive and controls but not in the cultures with Candida. We also report the molecular signature of tuberculosis infection, in ATBI patients, the following genes were found to be up-regulated and absent in LTBI individuals: two kinases (JAK3 and p38MAPK), four interleukins (IL-7, IL-2, IL-6, and IFNbeta1), a chemokine (HCC-4) a chemokine receptor (CxCR5), two interleukin receptors (IL-1R2 and IL-18R1), and three additional ones (TRAF5, Smad2, CIITA, and NOS2A). By contrast, IL-17 and IGFBP3 were significantly up-regulated in LTBI. And, STAT4, GATA3, Fra-1, and ICOS were down-regulated in ATBI but absent in LTBI. Conversely, TLR-10, IL-15, DORA, and IKK-beta were down-regulated in LTBI but not in ATBI. Interestingly, the majority of the up-regulated genes found in ATBI were found in cultures stimulated with tuberculin (PPD) or Candida antigens, suggesting that these pathogens stimulate similar immunological pathways. We believe that the molecular signature distinguishing active from latent tuberculosis infection may require using cytokine bead arrays along with RNA microarrays testing cell cultures at different times following in vitro proliferation assays using several bacterial antigens and PPD.
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PMID:Molecular signatures distinguishing active from latent tuberculosis in peripheral blood mononuclear cells, after in vitro antigenic stimulation with purified protein derivative of tuberculin (PPD) or Candida: a preliminary report. 1864 50

IL-17A has been shown to be expressed at higher levels in respiratory secretions from asthmatics and to correlate with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease, the mechanism remains unknown. We previously demonstrated that IL-17A mediates CC chemokine (CCL11) production from human airway smooth muscle (ASM) cells. In this study, we demonstrate that STAT3 activation is critical in IL-17A-mediated CCL11 expression in ASM cells. IL-17A mediated a rapid phosphorylation of STAT3 but not STAT6 or STAT5 in ASM cells. Interestingly, transient transfection with wild-type or mutated CCL11 promoter constructs showed that IL-17A-mediated CCL11 expression relies on the STAT6 binding site. However, STAT3 but not STAT6 in vivo binding to the CCL11 promoter was detected following IL-17A stimulation of ASM cells. Overexpression of DN STAT3 (STAT3beta) abolishes IL-17A-induced CCL11 promoter activity. This effect was not observed with STAT6 DN or the STAT3 mutant at Ser(727). Interestingly, disruption of STAT3 activity with the SH2 domain binding peptide, but not with control peptide, results in a significant reduction of IL-17A-mediated STAT3 phosphorylation and CCL11 promoter activity. IL-17A-mediated CCL11 promoter activity and mRNA were significantly diminished in STAT3- but not STAT6-silenced ASM cells. Finally, IL-17A-induced STAT3 phosphorylation was sensitive to pharmacological inhibitors of JAK2 and ERK1/2. Taken together, our data provide the first evidence of IL-17A-mediated gene expression via STAT3 in ASM cells. Collectively, our results raise the possibility that the IL-17A/STAT3 signaling pathway may play a crucial role in airway inflammatory responses.
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PMID:Critical role for STAT3 in IL-17A-mediated CCL11 expression in human airway smooth muscle cells. 1926 12

The Mycobacterium tuberculosis early secreted Ag of 6 kDa (ESAT-6) is a potent Ag for human T cells and is a putative vaccine candidate. However, ESAT-6 also contributes to virulence in animal models, mediates cellular cytolysis, and inhibits IL-12 production by mononuclear phagocytes. We evaluated the effects of ESAT-6 and its molecular chaperone, culture filtrate protein of 10 kDa (CFP10), on the capacity of human T cells to produce IFN-gamma and proliferate in response to TCR activation. Recombinant ESAT-6, but not CFP10, markedly inhibited IFN-gamma production by T cells stimulated with M. tuberculosis or with the combination of anti-CD3 and anti-CD28, in a dose-dependent manner. ESAT-6 also inhibited T cell production of IL-17 and TNF-alpha but not IL-2. Preincubation of ESAT-6 with CFP10 under conditions that favor dimer formation did not affect inhibition of IFN-gamma. ESAT-6 decreased IFN-gamma transcription and reduced expression of the transcription factors, ATF-2 and c-Jun, which normally bind to the IFN-gamma proximal promoter and stimulate mRNA expression. ESAT-6 inhibited T cell IFN-gamma secretion through mechanisms that did not involve cellular cytotoxicity or apoptosis. ESAT-6, but not CFP10, bound to T cells and inhibited expression of early activation markers without reducing activation of ZAP70. We conclude that ESAT-6 directly inhibits human T cell responses to mycobacterial Ags by affecting TCR signaling pathways downstream of ZAP70.
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PMID:ESAT-6 inhibits production of IFN-gamma by Mycobacterium tuberculosis-responsive human T cells. 1926 45

IL-24 is a member of the IL-10 family of cytokines. In this study, we investigated IL-24 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD), and characterized the molecular mechanisms responsible for IL-24 expression in human colonic subepithelial myofibroblasts (SEMFs). IL-24 expression in the IBD mucosa was evaluated by immunohistochemical methods. IL-24 mRNA and protein expression was determined by real-time PCR and ELISA, respectively. AP-1 and C/EBP DNA-binding activity and IL-24 promoter activity were assessed by EMSA analysis and a reporter gene assay, respectively. IL-24 mRNA expression was significantly elevated in active lesions from patients who have ulcerative colitis and Crohn's disease. Colonic SEMFs were identified as a major source of IL-24 in the mucosa. IL-1beta, but not IL-17A, TNF-alpha, or IFN-gamma, significantly enhanced IL-24 mRNA and protein expression in isolated colonic SEMFs. The IL-1beta-induced IL-24 mRNA expression was mediated by the activation of the transcription factors, AP-1 and C/EBP-beta. Induction of IL-24 mRNA stabilization was also involved in the effects of IL-1beta. IL-24 induced JAK1/STAT-3 phosphorylation and SOCS3 expression in HT-29 colonic epithelial cells. IL-24 did not modulate the proliferation of HT-29 cells, but significantly increased the mRNA expression of membrane-bound mucins (MUC1, MUC3, and MUC4). IL-24 derived from colonic SEMFs acts on colonic epithelial cells to elicit JAK1/STAT-3 activation and the expression of SOCS3 and mucins, supporting their suppressive effects on mucosal inflammation in IBD.
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PMID:Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease. 1953 21

Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORgammat, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1beta, IL6, IL21 and IL23. Recent studies indicate that TGFbeta is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFbeta reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.
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PMID:Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease. 1959 95

JAK3, a member of the Janus kinase family, is predominantly expressed in hemopoietic cells and binds specifically to the common gamma chain of a subfamily of cytokine receptors that includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Previous studies suggest that this tyrosine kinase plays key roles in mediating T cell functions, and inhibition of JAK3 has been shown to prevent graft rejection and decrease the severity of arthritis in rodent models. However, the functions of JAK3 in the development of skin immune responses and diseases such as psoriasis have not been determined. CD18 mutant PL/J mice develop spontaneous T cell-dependent psoriasiform skin disease with several similarities to human psoriasis. In this study, we treated mice with established skin disease with R348, a small molecule inhibitor of JAK3, and observed a marked attenuation of skin lesions following 6 wk of treatment. Histological analyses revealed major reductions of both epidermal and dermal lesion severity scores in R348-treated CD18-deficient PL/J mice compared with vehicle controls, which was associated with decreased CD4(+) T cell infiltration. In addition, systemic levels of IL-17, IL-22, IL-23, and TNF-alpha were significantly lower in mice receiving the compound, and T cells isolated from R348-treated mice also showed reduced phosphorylation of Stat5 after stimulation with IL-2. These findings suggest that small-molecule inhibitors of JAK3 may be useful in the treatment of inflammatory skin diseases such as psoriasis and strongly implicate JAK signaling events as important in the pathogenesis of this disease.
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PMID:JAK3 inhibition significantly attenuates psoriasiform skin inflammation in CD18 mutant PL/J mice. 1959 99

The secreted proteins of M. tuberculosis, early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate protein 10 kDa (CFP10), have been identified as antigenic proteins with potent T-cell stimulatory effects, and therefore have been the focus of tuberculosis vaccine studies. However, recent work showed that secretion of these proteins by the specialized ESAT-6 secretion system (ESX)-1 of M. tuberculosis is associated with virulence and pathogenesis. The studies demonstrated that ESAT-6 inhibits antigen-presenting cell function by reducing IL-12 production by macrophages through interrupting TLR2 signaling pathways and inducing macrophage apoptosis. However, the effect of ESAT-6 on T cells remains unexplored. To address this question, we studied the effect of recombinant ESAT-6 and CFP10 on human primary T-cell IFN-gamma secretion and proliferation. ESAT-6, but not CFP10, inhibited IFN-gamma production by T cells stimulated with M. tuberculosis or with anti-CD3 plus anti-CD28, in a dose-dependent manner. ESAT-6 also inhibited T-cell production of IL-17 and TNF-a, but not IL-2. Presence of CFP10 as part of the ESAT-6/CFP10 heterodimer did not affect ESAT-6 inhibition of T-cell IFN-gamma production. ESAT-6 inhibited the proliferation of CD3+ cells in response to TCR stimulation. ESAT-6 decreased T-cell IFN-gamma secretion by mechanisms independent of cytotoxicity or apoptosis. ESAT-6 reduced IFN-gamma mRNA levels by inhibiting the expression of the transcription factors, ATF-2, c-Jun and CREB, which upregulate IFN-gamma gene expression in T cells through binding to the IFN-gamma proximal promoter. ESAT-6, but not CFP10, bound to T cells and inhibited expression of early activation markers without reducing phosphorylation of ZAP70, a proximal TCR signaling molecule. We conclude that ESAT-6 directly inhibits human T-cell responses by affecting TCR signaling pathways downstream of ZAP70.
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PMID:Mycobacterium tuberculosis ESX-1 system-secreted protein ESAT-6 but not CFP10 inhibits human T-cell immune responses. 2000 11


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