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-10 is an anti-inflammatory cytokine produced in the joint in rheumatoid arthritis by macrophages and infiltrating blood lymphocytes. Regulation of its expression is poorly understood, but previous findings have suggested that physical interactions with T cells may play a role. This report investigates signalling mechanisms involved in the production of macrophage IL-10 upon interaction with fixed, cytokine-stimulated T cells (Tck). Elutriated monocytes were differentiated to macrophages by macrophage-colony-stimulating factor (M-CSF) and co-cultured with fixed T cells chronically stimulated in a cytokine cocktail of IL-2/IL-6/tumour necrosis factor (TNF)-alpha in the presence or absence of wortmannin and LY294002, inhibitors of phosphatidylinositol 3-kinase (PI3K), or of rapamycin, an inhibitor of p70 S6-kinase (p70S6K). Spontaneous IL-10 production by rheumatoid arthritis synovial-membrane mononuclear cells (RA-SMCs) and co-cultures of rheumatoid arthritis T cells (RA-Ts) and macrophages was also assessed. RA-T and Tck induction of macrophage IL-10 production was suppressed by cell separation and inhibition of PI3K and p70S6K. PI3K involvement was also shown by phosphorylation of the downstream effector protein kinase B. Spontaneous IL-10 production by RA-SMCs was also inhibited by LY294002 and depletion of the nonadherent (T-cell-enriched) fraction of the cell population. IL-10 production in RA-SMCs and M-CSF-primed macrophages, activated by interaction with Tck, is PI3K- and p70S6K-dependent.
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PMID:Cytokine-stimulated T cells induce macrophage IL-10 production dependent on phosphatidylinositol 3-kinase and p70S6K: implications for rheumatoid arthritis. 1187 39

To explore the possible cross-talk between the IL-6 and TGF-beta1 pathways in AML blast cells, the effect of TGF-beta1 pretreatment on IL-6-induced STAT3 tyrosine phosphorylation was studied. A reduction of STAT3 tyrosine phosphorylation after TGF-beta1 pretreatment was observed in four out of 40 AML cases (10%), although all of the AML cases responded to TGF-beta1 by means of SMAD3 translocation. The reduced IL-6-mediated STAT3 tyrosine phosphorylation after pre-treatment with TGF-beta1 was associated with apoptosis and coincided with the degradation of certain cellular proteins, including JAK1 and -2 and Tyk2, without affecting the ERK expression and phosphorylation. Furthermore, treatment of AML blasts with the cytostatic agent VP16, as an alternative way to induce apoptosis, resulted in a similar degree of degradation of JAK kinases and concomitant reduction of IL-6-mediated STAT3 tyrosine phosphorylation. Although degradation of JAK kinases could be rescued by incubating the cells with the pan-caspase inhibitor Z-VAD-fmk, the attenuating effect of TGF-beta1 treatment on the STAT3 tyrosine phosphorylation was still partly present. It was shown that in AML cells cultured in the presence of Z-VAD-fmk, TGF-beta1 pretreatment resulted in a reduction of JAK1 phosphorylation upon IL-6 stimulation. Expression of SOCS1 and -3 could be ruled out as a possible cause of reduced JAK1 phosphorylation levels in the investigated AML case.
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PMID:Downregulation of IL-6-induced STAT3 tyrosine phosphorylation by TGF-beta1 is mediated by caspase-dependent and -independent processes. 1196 Mar 49

Although the area of research on the role of MCs in innate immunity is relatively new, a number of studies that are reviewed here provide substantial evidence that MCs play a critical role in host immune defense against gram-negative bacteria. The studies show that mast cells have the ability to recognize and engulf bacteria and they release a number of inflammatory mediators including interleukin (IL)-4, IL-6, IL-10, TNF alpha, and leukotrienes in response to bacterial challenge. MC-derived TNF alpha and leukotrienes are shown to be important for bacterial clearance and early recruitment of phagocytic help at the site of infection. Studies directed at elucidating the molecular mechanisms associated with mast cell recognition of bacteria and subsequent events leading to mast cell mediator release revealed that GPI anchored CD48 molecule present on the cell surface of mast cells serves as a receptor for the bacterial adhesion molecule, FimH. The ligation of CD48 receptor by FimH-expressing bacteria results in bacterial uptake into caveolar chambers. This distinct mechanism of bacterial uptake promotes bacterial survival inside the cytosol of the mast cells. Although the exact mechanism(s) of how MC-dependent inflammatory responses are regulated is currently not known, recent studies have shown that complement, CD11 beta/CD18 (Mac-1) and protein tyrosine kinase JAK3, and TLR4 are important for the full expression of MC-dependent innate immunity in mice.
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PMID:Regulation of mast cell-mediated innate immunity during early response to bacterial infection. 1197 23

IL-6 is a multifunctional cytokine involved in regulation of differentiation, antibody production, and growth of certain types of tumor cells. Its excessive production plays a major role in pathogenesis of multiple myeloma and postmenopausal osteoporosis. In the course of a screening program aimed at IL-6 inhibitor from microbial products, we found madindoline A (MDL-A) and madindoline B, which have a fuloindoline structure with diketocyclopentene bound to the methyl group. MDL-A has no cytotoxic activities. It inhibited only activities of both IL-6 and IL-11 without affecting the IL-6-specific signal transduction cascade, JAK2/STAT3. In a dose-dependent manner [(3)H]MDL-A binds to gp130, which is a signal transducing 130-kDa glycoprotein, but formation of the trimeric complex IL-6/IL-6 receptor/gp130 was not inhibited, suggesting that MDL-A suppresses dimerization of trimeric complexes. Not only did MDL-A markedly inhibit IL-6- and IL-11-induced osteoclastogenesis in vitro, but it also inhibited IL-6-stimulated serum amyloid A production and bone resorption in an experimental model of postmenopausal osteoporosis in vivo by a different mechanism from that of 17beta-estradiol. Here we show that MDL-A has a highly selective inhibitory effect on IL-6 and IL-11 activities by inhibiting a gp130 activity while suppressing bone loss in ovariectomized mice. MDL-A is anticipated as a lead compound for treatment of hormone-dependent postmenopausal osteoporosis, which has no serious side effects, and as a new mechanism of action, gp130 blocking.
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PMID:Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130. 1241 53

Signal transducers and activators of transcription (STAT) factors are cytoplasmic proteins that can be activated by Janus kinases (JAK) and that modulate gene expression in response to cytokine receptor stimulation. STAT proteins dimerize, translocate into the nucleus, and activate specific target genes. In the present study, we show for the first time that interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3 proteins in bovine articular chondrocytes. Western blotting and mobility shift assays demonstrated that this effect is accompanied by the DNA binding of the STAT proteins. The mitogen-activated protein kinase pathway was also activated in response to IL-6/sIL-6R association, as reflected by phosphorylation of ERK1 and ERK2 proteins. In these conditions, the expression of cartilage-specific matrix genes, type II collagen, aggrecan core, and link proteins was found to be markedly down-regulated. This negative effect was abolished by addition of parthenolide, an inhibitor of the STAT activation, whereas blockade of the MAP kinases with PD098059 was without significant effect. Thus, activation of the STAT signaling pathways, but not ERK-dependent pathways, is essential for down-regulation of the major cartilage-specific matrix genes by IL-6. In addition, a parallel reduction of Sox9 expression, a key factor of chondrocyte phenotype, was found in these experimental conditions. These IL-6 effects might contribute to the phenotype loss of chondrocytes in joint diseases and the alteration of articular cartilage associated with this pathology.
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PMID:JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression. 1241 23

Through the production of cytokines and growth factors the endothelium of secondary lymphoid organs plays a crucial role in controlling lymphocyte migration to the lymphoid microenvironment, an essential step in the initiation of the immune response. Here we demonstrate that direct contact of B cell lines with tonsil-derived human endothelial cells resulted in changes in the phosphorylation state of endothelial cells, causing their functional activation. We found a rapid (<15-s) and transient dephosphorylation, followed by a rapid rephosphorylation of tyrosine residues of the focal adhesion kinase, paxillin, and ERK2. Maximal rephosphorylation occurred after 15-30 min of B cell contact. Preincubation of lymphoid B cells with an adhesion-blocking Ab directed against alpha(4)beta(1) integrin abrogated adhesion-mediated changes of endothelial cell tyrosine phosphorylation, suggesting that cell contact was essential. Similar patterns of tyrosine phosphorylation, but with slightly different kinetics were induced after cross-linking of beta(1) integrin or CD40 on endothelial cells. Functional activation of endothelial cells by B cell adhesion was confirmed by the production of IL-6, IL-8, monocyte chemoattractant protein-1, M-CSF, and macrophage inflammatory protein-1beta mRNA. However, direct cross-linking of beta(1) integrin and CD40 failed to accomplish the same functional activation. These data indicate that direct contact of lymphoid B cells with the endothelium from lymphoid tissue induce endothelial cell signaling, resulting in chemokine and cytokine production. This phenomenon may provide a mechanism for the remodeling of the endothelium from lymphoid tissues, thus contributing to the free migration of lymphocytes and other cells into the lymphoid organs.
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PMID:Adhesion of B cell lines to endothelial cells from human lymphoid tissue modulates tyrosine phosphorylation and endothelial cell activation. 1242 71

Hematopoietic malignancies have been shown to depend on cytokine growth factor autocrine/paracrine loops for growth and differentiation. This results in the constitutive activation of cytokine-mediated transcription factors like signal transducer and activators of transcription (STAT) 3 in non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). Recent evidence demonstrates that cytokines also contribute to a drug-resistant phenotype in many tumor cell types. We hypothesized that inhibitors of the STAT3 pathway would sensitize drug-resistant and endogenous cytokine-dependent NHL and MM tumor cells to the cytotoxic effects of chemotherapeutic drugs. We examined an AIDS-related NHL cell line, 2F7, known to be dependent on interleukin (IL)-10 for survival and an MM cell line, U266, known to be dependent on IL-6 for survival. IL-10 and IL-6 signal the cells through the activation of Janus kinase (JAK)1 and JAK2, respectively. Thus, we investigated the effect of two chemical STAT3 pathway inhibitors, namely, piceatannol (JAK1/STAT3 inhibitor) and tyrphostin AG490 (JAK2/STAT3 inhibitor), on the tumor cells for sensitization to therapeutic drugs. We demonstrate by phosphoprotein immunoblotting analysis and electrophoretic mobility shift analysis that piceatannol and AG490 inhibit the constitutive activity of STAT3 in 2F7 and U266, respectively. Furthermore, piceatannol and AG490 sensitize 2F7 and U266 cells, respectively, to apoptosis by a range of therapeutic drugs including cisplatin, fludarabine, Adriamycin, and vinblastine. The specificity of the inhibitors was corroborated in experiments showing that piceatannol had no effect on U266 and, likewise, AG490 has no effect on 2F7. The sensitization observed by these inhibitors correlated with the inhibition of Bcl-2 expression in 2F7 and Bcl-xL expression in U266. Altogether, these results demonstrate that STAT3 pathway inhibitors are a novel class of chemotherapeutic sensitizing agents capable of reversing the drug-resistant phenotype of cytokine-dependent tumor cells.
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PMID:Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. 1253 84

Interleukin (IL)-6 decreases cardiac contractility via a nitric oxide (NO)-dependent pathway. However, mechanisms underlying IL-6-induced NO production remain unclear. JAK2/STAT3 and ERK1/2 are two well known signaling pathways activated by IL-6 in non-cardiac cells. However, these IL-6-activated pathways have not been identified in adult cardiac myocytes. In this study, we identified activation of these two pathways during IL-6 stimulation and examined their roles in IL-6-induced NO production and decrease in contractility of adult ventricular myocytes. IL-6 increased phosphorylation of STAT3 (at Tyr(705)) and ERK1/2 (at Tyr(204)) within 5 min that peaked at 15-30 min and returned to basal levels at 2 h. Phosphorylation of STAT3 was blocked by genistein, a protein tyrosine kinase inhibitor, and AG490, a JAK2 inhibitor, but not PD98059, an ERK1/2 kinase inhibitor. The phosphorylation of ERK1/2 was blocked by PD98059 and genistein but not AG490. Furthermore, IL-6 enhanced de novo synthesis of iNOS protein, increased NO production, and decreased cardiac contractility after 2 h of incubation. These effects were blocked by genistein and AG490 but not PD98059. We conclude that IL-6 activated independently the JAK2/STAT3 and ERK1/2 pathways, but only JAK2/STAT3 signaling mediated the NO-associated decrease in contractility.
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PMID:JAK2/STAT3, not ERK1/2, mediates interleukin-6-induced activation of inducible nitric-oxide synthase and decrease in contractility of adult ventricular myocytes. 1259 39

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

We recently discovered that a ubiquitous protein, high mobility group box 1 protein (HMGB1), is released by activated macrophages, and functions as a late mediator of lethal systemic inflammation. To elucidate mechanisms underlying the regulation of HMGB1 release, we examined the roles of other cytokines in induction of HMGB1 release in macrophage cell cultures. Macrophage migration inhibitory factor, macrophage-inflammatory protein 1beta, and IL-6 each failed to significantly induce the release of HMGB1 even at supraphysiological levels (up to 200 ng/ml). IFN-gamma, an immunoregulatory cytokine known to mediate the innate immune response, dose-dependently induced the release of HMGB1, TNF, and NO, but not other cytokines such as IL-1alpha, IL-1beta, or IL-6. Pharmacological suppression of TNF activity with neutralizing Abs, or genetic disruption of TNF expression (TNF knockout) partially (50-60%) inhibited IFN-gamma-mediated HMGB1 release. AG490, a specific inhibitor for Janus kinase 2 of the IFN-gamma signaling pathway, dose-dependently attenuated IFN-gamma-induced HMGB1 release. These data suggest that IFN-gamma plays an important role in the regulation of HMGB1 release through a TNF- and Janus kinase 2-dependent mechanism.
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PMID:IFN-gamma induces high mobility group box 1 protein release partly through a TNF-dependent mechanism. 1264 58


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