Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Ethyl pyruvate (EP) has been demonstrated to have an anti-inflammatory function. However, the molecular mechanisms underlying the anti-inflammatory action of EP are largely unknown. We here show that EP exerts its anti-inflammatory effect by inhibiting ROS-dependent STAT signaling through its antioxidant activity, like vitamin C or N-acetyl-L-cysteine. The inhibition of STAT1 and STAT3 by EP prevented their translocation to the nucleus and consequently inhibited expression of iNOS and COX-2 by inhibiting STAT1- and STAT3-mediated transcriptional activity, followed by changes in chromatin conformation via deacetylation of histones H3 and H4 in both gene promoters. EP also suppressed transcripts of other STAT-responsive inflammatory genes such as IL-1beta, IL-6, TNF-alpha, and MCP-1. We further found that the mechanism of inhibition of STAT1 and STAT3 by EP is due to inhibition of JAK2 through Rac1 inactivation and SOCS1 induction. These findings offer new therapeutic possibilities for EP based on a better understanding of the mechanism underlying the action of EP.
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PMID:Ethyl pyruvate has an anti-inflammatory effect by inhibiting ROS-dependent STAT signaling in activated microglia. 1862 1

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

Increased levels of particulate matter have been associated with adverse effects in the respiratory as well as the cardiovascular system. The biological mechanisms behind these associations are still unresolved. Among potential mechanisms, particulate matter-associated cardiac effects may be initiated by inhaled small-sized particles, particle components and/or mediators related to inflammation that translocate into the pulmonary circulation. In the present study cytokine responses (interleukin [IL]-6, IL-1beta, and tumor necrosis factor [TNF]-alpha) of primary rat cardiomyocytes and cardiofibroblasts in mono- and cocultures induced by direct exposure to particles, were compared with cytokine responses induced by mediators released by particle-exposed primary rat epithelial lung cells (conditioned media). Cells were exposed to a model ultrafine particle (ultrafine carbon black, Printex 90) and in selected experiments to an urban air particle sample (SRM 1648, St Louis, MO). In lung cell cultures both particle types induced release of IL-6 and IL-1beta, whereas TNF-alpha was only detected upon exposure to St Louis particles. The release of IL-6 by cardiac cells was strongly enhanced upon exposure to conditioned media, and markedly exceeded the response to direct particle exposure. IL-1, but not TNF-alpha, seemed necessary, but not sufficient, for this enhanced IL-6 release. The role of IL-1 was demonstrated by use of an IL-1 receptor antagonist that partially reduced the effect of the conditioned media, and by a stimulating effect on the cardiac cell release of IL-6 by exogenous addition of IL-1alpha and IL-1beta. These in vitro findings lend support to the hypothesis that particle-induced cardiac inflammation and disease may involve lung-derived mediators.
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PMID:Particle-induced cytokine responses in cardiac cell cultures--the effect of particles versus soluble mediators released by particle-exposed lung cells. 1870 Feb 32

The present study shows that JAK2-STAT3 inflammatory signaling mediates thrombin-stimulated microglia activation. In rat primary microglia, thrombin rapidly activated JAK2 and induced phosphorylation of STAT3. In addition, thrombin increased transcription of the inflammation-associated genes tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS), production of TNF-alpha, NO and induced neurodegeneration of dopaminergic neurons in mesencephalic cultures. AG490, a JAK inhibitor, markedly reduced activation of JAK2 and STAT3 in thrombin-treated microglia. AG490 also inhibited thrombin-induced transcription and expression of TNF-alpha, iNOS and/or NO release, moreover rescued dopaminergic neurons. These results suggest that JAK2-STAT3 signaling pathway plays a critical role in mediating thrombin-induced activation of microglia and degeneration of dopaminergic neurons.
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PMID:JAK2-STAT3 signaling pathway mediates thrombin-induced proinflammatory actions of microglia in vitro. 1871 Jul 87

Bruton's tyrosine kinase (Btk) represents an important signaling element downstream of ITAM-containing receptors, e.g. FcepsilonR1 and BCR. Btk is part of the calcium signalosome and thus, critically involved in intracellular calcium mobilization. Loss of Btk or expression of mutant forms results in severe disease phenotypes, X-linked agammaglobulinemia (XLA) and Xid in humans and mice, respectively. Previously, roles for Btk in TLR-mediated signal transduction have been found in monocytes/macrophages. In the present study we show that Btk deficiency moderately enhances or has no influence on the LPS- or lipopeptide-induced secretion of IL-6 and TNF-alpha from murine bone marrow-derived mast cells (BMMCs). Furthermore, activation of p38 kinase, which is required for cytokine production, is comparable in WT and Btk-/- BMMCs. Moreover, stability of the adaptor protein Mal as well as LPS-induced H(2)O(2) production does not vary between WT and Btk-/- cells. Interestingly, PKC-beta deficiency, which results in a Xid-like phenotype as well, has also no negative effect on LPS-induced cytokine secretion, suggesting that proteins of the calcium signalosome are not involved in TLR-mediated BMMC activation. In conclusion, the study reveals that Btk is dispensable for TLR signaling and function in murine BMMCs.
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PMID:Bruton's tyrosine kinase is dispensable for the Toll-like receptor-mediated activation of mast cells. 1884 85

Cytosolic alterations of calcium ion concentrations are an integral part of signal transduction. Similar functions have been hypothesized for other metal ions, in particular zinc (Zn(2+)), but this still awaits experimental verification. Zn(2+) is important for multiple cellular functions, especially in the immune system. Among other effects, it influences formation and secretion of pro-inflammatory cytokines, including TNF-alpha. Here we demonstrate that these effects are due to a physiological signaling system involving intracellular Zn(2+) signals. An increase of the intracellular zinc ion concentration occurs upon stimulation of human leukocytes with Escherichia coli, LPS, Pam(3)CSK(4), TNF-alpha, or insulin, predominantly in monocytes. Chelating this zinc signal with the membrane permeable zinc-specific chelator TPEN (N,N,N',N'-tetrakis-(2-pyridyl-methyl)ethylenediamine) completely blocks activation of LPS-induced signaling pathways involving p38 MAPK, ERK1/2, and NF-kappaB, and abrogates the release of proinflammatory cytokines, including TNF-alpha. This function of Zn(2+) is not limited to monocytes or even the immune system, but seems to be another generalized signaling system based on intracellular fluctuations of metal ion concentrations, acting parallel to Ca(2+).
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PMID:Zinc signals are essential for lipopolysaccharide-induced signal transduction in monocytes. 1894 Dec 40

Obesity is associated with chronic low-grade inflammation. It is currently hypothesized that products secreted from fat cells not only cause this proinflammatory condition but may also have a direct impact on the development of insulin resistance in skeletal muscle. The aim of this study was to investigate if adipocyte-conditioned media interfere with insulin-stimulated Akt/PKB phosphorylation in in vitro differentiated human skeletal muscle cells. Primary human skeletal muscle cells were exposed to adipocyte-conditioned media from subjects with a wide range of BMI. Insulin-induced phosphorylation of the signaling proteins Akt/PKB and ERK-2 was analyzed using a bead-based fluorescence detection system and was correlated to BMI and fat cell size. Adipocyte-conditioned media reduced insulin-stimulated Akt/PKB phosphorylation in a manner depending on BMI and fat cell volume. This inhibition in serine phosphorylation was comparable to that observed in TNF-alpha-treated control cultures. Conditioned media from omental adipocytes reduced Akt/PKB phosphorylation moderately to a greater extent compared to media from subcutaneous fat cells from the same donors (p<0.05). Furthermore, there were significant associations between the concentration of selected adipokines and Akt/PKB phosphorylation. These data provide first direct evidence that secreted factors from freshly isolated mature fat cells separated according fat cell size reduce insulin-stimulated Akt/PKB phosphorylation in human skeletal muscle cells and may contribute to the pathogenesis of obesity-associated insulin resistance.
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PMID:Effect of conditioned media from mature human adipocytes on insulin-stimulated Akt/PKB phosphorylation in human skeletal muscle cells: role of BMI and fat cell size. 1895 3

The recruitment of leukocytes to injured tissue is crucial for the initiation of inflammatory responses as well as for immune surveillance to fight tumor progression. In this study, we show that oncostatin M, a member of the IL-6-type cytokine family and potent proinflammatory cytokine stimulates the expression of the chemokines CCL1, CCL7, and CCL8 in primary human dermal fibroblasts at a faster kinetic than IL-1beta or TNF-alpha. The production of CCL1 and CCL8 is important for migration of monocytes, while specific Abs against CCL1 additionally inhibit the migration of T lymphocytes. We identify the mitogen-activated protein kinases ERK1/2 and p38 as crucial factors for the enhanced expression of CCL1 and CCL8. Depletion of the ERK1/2 target genes c-Jun or c-Fos strongly decrease CCL1 and CCL8 expression, while p38 MAPK prolongs the half-life of CCL1, CCL7, and CCL8 mRNA through inhibition of tristetraprolin. None of the STAT transcription factors STAT1, STAT3, or STAT5 stimulate transcription of CCL1 or CCL8. However, we identify a negative regulatory function of activated STAT5 for the gene expression of CCL1. Importantly, not STAT5 itself, but its target gene cytokine inducible SH2-domain containing protein is required for the STAT5 inhibitory effect on CCL1 expression. Finally, we show that constitutive activation of STAT5 through a mutated form of JAK2 (JAK2 V617F) occurring in patients with myeloproliferative disorders similarly suppresses CCL1 expression. Taken together, we identify novel important inflammatory target genes of OSM which are independent of STAT signaling per se, but depend on MAPK activation and are partly repressed through STAT5-dependent expression of cytokine inducible SH2-domain containing protein.
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PMID:Oncostatin M-induced and constitutive activation of the JAK2/STAT5/CIS pathway suppresses CCL1, but not CCL7 and CCL8, chemokine expression. 1898 Nov 57

The immunomodulatory properties of growth hormone (GH) are well recognized. Enhanced production of NO and cytokines by macrophages on treatment with GH was reported by us recently. The present investigation elucidates the signaling mechanism(s) by which GH activates macrophages in vitro. It is observed that GH induces the phosphorylation (activation) of JAK2, PI3K, PKC and MAP kinases. Studies with pharmacological inhibitors of various signaling molecules also indicated that GH-induced proinflammatory responses in macrophages are mediated by JAK2/PI3K/PKC/ERK1/2, JAK2/JNK and JAK/STAT signaling cascades. It was further observed that GH induced the enhanced expression/phosphorylation of transcription factors c-fos, c-jun, Elk-1 and Stat1. It is also demonstrated that GH-induced ERK1/2 cascade regulates the production of TNF-alpha and IL-1beta in macrophages, whereas JNK cascade mediated the production of TNF-alpha, IFN-gamma and IL-12. These results suggest that JAK2 plays a central role in mediating proinflammatory responses of macrophages on GH treatment.
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PMID:Growth hormone-induced production of cytokines in murine peritoneal macrophages in vitro: role of JAK/STAT, PI3K, PKC and MAP kinases. 1925 Jun 98


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