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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adherence of cells to microvascular endothelium is important in a number of processes, including inflammatory responses and metastasis. It has been demonstrated that in human models, cytokines such as TNF, IL-1, IFN-gamma increase the adhesiveness of endothelium for cells of the immune and inflammatory system by stimulating the expression of cell adhesion molecules on endothelial cell surfaces. We and others have shown similar cytokine-induced endothelial adhesiveness for tumor cells in murine and human models. In contrast to the effect of those modulators, transforming growth factor-beta (TGF-beta) has been shown to inhibit the binding of human neutrophils and T lymphocytes to human endothelium, although the mechanism of TGF-beta action remains unknown. Little is known about the effect of TGF-beta on tumor cell-endothelial interaction. In the present study, we demonstrate that TGF-beta inhibits basal and TNF-enhanced binding of murine P815 mastocytoma cells to murine microvascular endothelium (MME). The alterations in MME mediated by TGF-beta, also lead to the inhibition of adherence of murine splenocytes, thymocytes, and human lymphoblastoid cells but do not inhibit adherence of murine B16 melanoma cells. The effect of TGF-beta is transient and inhibition of the endothelial adhesive phenotype is strongest 12 to 24 h after addition of the factor to MME. The TGF-beta-mediated inhibition of P815 basal binding to endothelium is dependent on protein synthesis because cycloheximide reverses the TGF-beta effect. TGF-beta does not appear to activate classical signal transduction pathways. Inhibitors of G proteins do not abolish TGF-beta action, protein kinase C and protein kinase A activators elicit an effect opposite to that of the factor, TGF-beta does not increase intracellular cAMP levels, and finally calcium-mobilizing agents do not mimic, but rather inhibit the effect of TGF-beta. However, TGF-beta-mediated inhibition of both basal binding and TNF-enhanced P815 binding to MME is completely abolished in the presence of the protein phosphatase inhibitor okadaic acid which suggests that TGF-beta may elicit its effect by stimulating protein phosphatase activity.
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PMID:Inhibition of basal and tumor necrosis factor-enhanced binding of murine tumor cells to murine endothelium by transforming growth factor-beta 1. 131 61

In Swiss 3T3 murine fibroblasts, interleukin 1 (IL-1) and bradykinin stimulate prostaglandin E2 (PGE2) synthesis. However, in the present study, we found that neither agonist stimulated PGE2 synthesis in BALB/c 3T3 murine fibroblasts, this in spite of expression of similar numbers of receptors for each agonist compared to Swiss 3T3 cells. When BALB/c 3T3 cells were preincubated with cAMP analogs, both IL-1 and bradykinin stimulated PGE2 synthesis to levels similar to those observed in Swiss 3T3 cells. Similarly, when the cells were preincubated with forskolin, which activates the catalytic subunit of adenylate cyclase directly, or NECA, which stimulates cellular cAMP accumulation by activating adenosine receptors, IL-1 and bradykinin stimulated PGE2 synthesis. Rp-cAMPS, an inhibitor of cAMP-dependent protein kinase, blocked the ability of cAMP or NECA to render cells responsive to IL-1 and bradykinin. In basal BALB/c 3T3 cells, bradykinin and IL-1 stimulated arachidonate release in the absence of cAMP, but little conversion of released arachidonate to PGE2 occurred. cAMP, forskolin, and NECA all increased cyclooxygenase activity in the cells. SV-T2 is a clonal line originating from BALB/c 3T3 transformed with SV-40. In these cells, IL-1 and bradykinin stimulated PGE2 synthesis despite basal intracellular cAMP concentrations similar to BALB/c, and cAMP only modestly potentiated the response. In summary, cyclooxygenase expression appears to be regulated by cAMP in BALB/c 3T3 cells, and SV-40 transformation results in increased cyclooxygenase expression, apparently independent of cAMP.
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PMID:Elevated cAMP is required for stimulation of eicosanoid synthesis by interleukin 1 and bradykinin in BALB/c 3T3 fibroblasts. 133 33

Monocyte influx and activation in synovial joints are important in the pathogenesis of both degenerative and inflammatory arthropathies. In this study, we demonstrate the potential of articular cartilage to directly modulate these events. IL-1-stimulated human articular chondrocytes transcribed 0.7-kb monocyte chemoattractant protein-1 (MCP-1) mRNA. In situ hybridization of cartilage organ cultures revealed MCP-1 transcripts in chondrocytes in the superficial tangential zone within 2 h of stimulation with IL-1. Chondrocytes in deeper layers responded by 4 h and reached maximum MCP-1 mRNA levels by 8-12 h. IL-1-stimulated cartilage organ and chondrocyte monolayer cultures released functional monocyte chemotactic activity. This was neutralized by a monoclonal antibody specific for MCP-1, and was associated with the synthesis and secretion of immunoreactive 13-kD and 15-kD isoforms of MCP-1. Regulators and signal transduction pathways involved with the expression of the MCP-1 gene in chondrocytes were analyzed. Steady-state mRNA levels were increased by the known chondrocyte activators IL-1, tumor necrosis factor alpha, LPS, platelet-derived growth factor, and transforming growth factor beta. In addition, leukemia inhibitory factor induced MCP-1 gene expression and protein synthesis, identifying this cytokine as a new regulator of chondrocyte function. Dexamethasone blunted the induction of MCP-1 gene expression by IL-1 and by activators of protein kinase A as well as protein kinase C signal transduction pathways. In contrast, retinoic acid strongly increased phorbol myristate acetate-induced MCP-1 expression and potentiated the effects of IL-1 and LPS. In conclusion, chondrocytes express MCP-1 in response to factors that are present in cartilage or synovium. This provides a mechanism by which cartilage can play an active role in the initiation and progression of arthritis.
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PMID:Monocyte chemoattractant protein-1 (MCP-1) expression in human articular cartilage. Induction by peptide regulatory factors and differential effects of dexamethasone and retinoic acid. 136 41

The pattern of expression of at least four neuropeptides contained in adrenomedullary chromaffin cells is altered by exposure to the cytokines interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF alpha), alone or in combination with stimulation of other second messenger pathways. Vasoactive intestinal polypeptide (VIP) was elevated 2- to 3-fold by 1 nM IL-1 alpha within 48 h of exposure, while neurotensin and substance P synthesis were unaffected, and met-enkephalin levels were decreased 25-35%. Stimulation of VIP and substance P biosynthesis by forskolin was markedly enhanced by IL-1 alpha, while forskolin stimulation of enkephalin and neurotensin biosynthesis was unaffected. IL-1 alpha amplified the effect of phorbol myristate acetate to increase the VIP content of chromaffin cells, but antagonized phorbol ester-induced elevation of neurotensin levels. TNF alpha also demonstrated a neuropeptide-specific pattern of modulation of second-messenger effects on chromaffin cell neuropeptide levels similar to those seen with IL-1 alpha. The neuroendocrine actions of IL-1 alpha described above, unlike IL-1 action in the immune system, do not appear to be mediated through IL-2 as this cytokine did not affect VIP or enkephalin expression in the presence or absence of protein kinase stimulation. Neither IL-1 alpha nor TNF alpha affected the calcium-coupled stimulation of neuropeptide secretion and biosynthesis that occurs in response to cell depolarization in these and other neuroendocrine cells in vitro and in vivo. These data provide a functional demonstration of IL-1 and TNF receptors in chromaffin cell cultures and suggest a physiological role for cytokine production in the adrenal medulla. Since both the magnitude and direction of neuropeptide synthesis modulation by IL-1 alpha and TNF alpha are highly peptide-specific, it appears that these cytokines do not merely augment second messenger pathways that affect neuropeptide synthesis, but potentially regulate the activity of factors controlling the pattern of neuropeptide gene expression in chromaffin cells.
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PMID:Interleukin-1 alpha and tumor necrosis factor-alpha differentially regulate enkephalin, vasoactive intestinal polypeptide, neurotensin, and substance P biosynthesis in chromaffin cells. 137 39

Recent cloning of human and murine IL-1 receptor (IL-1R) has revealed that there are at least two type of IL-1R: type I IL-1R is detected on T cells and fibroblasts and consists of 552 AAs with a cytoplasmic domain of 213 AAs, while type II is detected on B cells and monocytic cell lines and consists of 398 AAs with a short stretch intracytoplasmic domain of 29 AAs. Extracytoplasmic portion of IL-1R has some homology with vaccinia virus B15 Ag or fibroblast protein ST-2, while cytoplasmic portion has considerable similarity with Drosophila toll gene. By transfecting murine type I IL-1R cDNA into a human Jurkat cell line, structural and functional potion required for the IL-1 signal transduction is determined. At least broad portion of cytoplasmic domain including 364-474 AAs from N-terminus are found to be essential, while PKC acceptor site (Ser-431 and Ser-509), and PKA acceptor site (Ser-528) are not essential for the IL-8 gene expression.
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PMID:[Function, molecular structure and gene expression of interleukin-1]. 143 66

The mechanism by which interleukin-1 alpha (IL-1 alpha) activates NF-kappa B DNA-binding activity is not completely understood. While it is well established that protein kinase C can activate NF-kappa B, neither protein kinase C nor protein kinase A appears to be critical in the induction of NF-kappa B by IL-1 alpha. Since a number of growth factors signal via protein tyrosine kinase, in this study we examined a possible involvement of protein tyrosine kinase in the IL-1 alpha-induced NF-kappa B. The results showed that in the murine pre-B cell line 70Z/3 and in the murine T cell line EL-4 6.1 C10 IL-1 alpha-induced NF-kappa B was associated with transient increase in protein tyrosine kinase activity. Pre-treatment of these cell lines with herbimycin A, an inhibitor of tyrosine kinase activity, blocked the IL-1 alpha-enhanced protein tyrosine kinase activity and the IL-1 alpha-induced NF-kappa B DNA-binding activity. Herbimycin A at concentrations sufficient to block IL-1 alpha-induced NF-kappa B did not block the phorbol 12-myristate 13-acetate (PMA)-induced NF-kappa B. The data suggest that IL-1 alpha and PMA activate NF-kappa B by different pathways and that induction of NF-kappa B DNA-binding activity by IL-1 might be dependent on protein tyrosine phosphorylation.
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PMID:Herbimycin A blocks IL-1-induced NF-kappa B DNA-binding activity in lymphoid cell lines. 154 54

This study analyzes the expression of monocyte chemoattractant protein-1 (MCP-1) by inflamed synovial tissue and defines its regulation in cultured synoviocytes. Synoviocytes from patients with rheumatoid arthritis and osteoarthritis express the 0.7-kb MCP-1 mRNA. Stimulation of synoviocytes with IL-1, TNF-alpha, LPS, platelet-derived growth factor, and transforming growth factor-beta-1, but not with basic fibroblast growth factor causes a marked increase in MCP-1 mRNA levels. Expression of the MCP-1 gene is inducible by activators of the protein kinase A (cAMP) and C (PMA) signal transduction pathways and is differentially regulated by the steroids dexamethasone and retinoic acid. Cultured synoviocytes de novo synthesize 12-, 15-, and 15.2-kDa MCP-1 proteins, which increase after stimulation with IL-1. Synovial tissues from donors without joint disease and from patients with rheumatoid or osteoarthritis were analyzed for MCP-1 mRNA expression by in situ hybridization. In these samples MCP-1 mRNA expressing cells were predominantly found in the sublining cell layers, whereas specimens of normal synovial tissue contained only few positive cells. These results identify synoviocytes as a source of MCP-1. Its expression is controlled by peptide regulatory factors that are known to be present in arthritic joints. Detection of cells producing MCP-1 mRNA in synovial tissues from patients with arthritis shows that this gene is expressed in vivo and suggests that MCP-1 can play a role in recruiting monocytes in joint inflammation.
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PMID:Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes. 162 9

High resolution two-dimensional gel electrophoresis was used to analyze the signal transduction pathways of tumor necrosis factor (TNF-alpha) and interleukin 1 (IL-1 alpha and -beta) in human fibroblasts. Approximately 450 discrete radioactive spots were electrophoretically resolved from cytosolic extracts of cells prelabeled with 32P. At least 63 of these polypeptides exhibited significant and concordant phosphorylation or dephosphorylation in response to TNF or IL-1, despite the fact that different receptors are involved. Most of these changes concerned serine/threonine residues although enhanced tyrosine phosphorylation of several polypeptides was also observed. Phosphorylation patterns induced by a number of other agonists were compared with the patterns induced by IL-1 and TNF. These included activators of protein kinases C and A, bradykinin (a stimulator of inositol phospholipid hydrolysis), epidermal growth factor, heatshock, and mellitin (an activator of phospholipase A2). Although each of these agonists induced changes resulting in a distinct pattern of protein phosphorylation, none of these patterns had significant homology with that induced by IL-1 and TNF. Other assays were performed to verify the involvement of specific kinases. Collectively, these data indicate that IL-1 and TNF activate multiple protein kinases viz. a kinase(s) which activates microtubule-associated protein 2 (MAP-2) kinase, a kinase that phosphorylates the cap-binding protein, and a possibly novel serine/threonine protein kinase.
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PMID:Interleukin 1 and tumor necrosis factor activate common multiple protein kinases in human fibroblasts. 165 Mar 57

The antimalignant cell activity of tumor necrosis factor (TNF) in many cell types can be enhanced by lithium chloride (LiCl). This study shows the in vitro effect of LiCl on the TNF-induced or interleukin 1 (IL-1)-induced expression of IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-3, IL-2, and the IL-2 receptor-alpha (IL-2R alpha). The levels of IL-6 and GM-CSF in the medium of TNF-treated L929 fibrosarcoma cells were increased by cotreatment with LiCl. In contrast, enhancement of IL-6 production by dibutyryl cyclic AMP or cycloheximide was not affected by LiCl. The production of IL-6 and GM-CSF was not correlated with sensitivity to TNF-mediated cell killing. IL-1 by itself had no measurable effects on L929 cells. However, LiCl potentiated the IL-1-induced synthesis of IL-6, GM-CSF, IL-3, and IL-2 in PC60 murine T-cell hybridoma cells. TNF alone induced only GM-CSF production in these cells, but in the presence of LiCl, increased amounts of GM-CSF as well as small amounts of IL-2 and IL-6 could be detected. It is also shown that in these PC60 cells the expression of the IL-2R alpha was induced by TNF + LiCl treatment but not by TNF alone. IL-2R alpha expression was likewise considerably enhanced by IL-1 + LiCl treatment, as compared with treatment with IL-1 alone. The effects of LiCl on the TNF-induced and the IL-1-induced gene expression seem to be independent of the protein kinase A and C pathways. These results show that LiCl can modulate both TNF-mediated cytotoxicity and TNF-induced and IL-1-induced cytokine expression, suggesting that Li+ acts early in the TNF-signaling pathway, but at a step shared with the IL-1-signaling pathway.
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PMID:Lithium chloride potentiates tumor necrosis factor-induced and interleukin 1-induced cytokine and cytokine receptor expression. 165 81

We have previously described an Ia-expressing macrophage hybridoma clone, termed clone 59, which attains the ability to induce Ts cells after activation with murine rIFN-gamma. In this report, we show that a protein kinase C (PKC) activator, PMA (10 ng/ml) can replace IFN-gamma in inducing this form of macrophage competence. IFN-gamma-induced cellular competence was abrogated specifically by a PKC inhibitor but not by inhibitors that have specificity for cyclic nucleotide-dependent protein kinases. Furthermore, PGE2 known to induce protein kinase A in murine macrophages also failed to induce competence. In contrast, the ability to induce Th responses was neither dependent on IFN-gamma nor inhibited by prior treatment with protein kinase inhibitors. Furthermore, PKC depletion of macrophages by treatment with high doses (100 ng/ml) of PMA abrogated their ability to induce Ts cells. In addition, PKC-depleted macrophages failed to regain the ability to stimulate Ts cells after further treatment with IFN-gamma. The ability of IFN-gamma to modulate macrophage-mediated induction of Ts cells does not clearly correlate with an increased Ia expression as inducible expression of Ia was not consistently abrogated by PKC inhibitor treatment. In addition, PKC inhibitors failed to prevent the production of the cytokines IL-1 and IL-6. However, incubation of IFN-gamma or PMA-treated macrophages with antibodies recognizing the putative IJ ligand blocked the ability to induce Ts cells, suggesting the expression of these determinants on accessory cells is responsible for Ts induction.
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PMID:Involvement of protein kinase C in competence induction of macrophages to generate T suppressor cells. 171 Feb 37


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