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)

Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensitivity to Avemar, a fermented wheat germ extract. Avemar synergized with lipopolysaccharide and PMA in the induction of the transcription of cytokine genes and release of inflammatory cytokines. At higher concentrations the preparation had a significant negative effect on the proliferation and survival of activated myeloid cell types. Avemar treatment induced the synthesis of ICAM-1 and synergized with the ICAM-inducing effect of TNF, but had no effect on VCAM-1 expression on microvascular endothelial cells. The effect of Avemar on signaling pathways, which are involved in cell activation was studied on HeLa cells as a model system. Avemar treatment increased the activity of stress kinases in a concentration-dependent way, resulting in the activation of AP-1 transcription factor. NF-kappa B-sensitive reporters were also activated by Avemar; in contrast, no effect of the preparation was observed on PKA-sensitive signaling pathways.
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PMID:Synergistic effect of Avemar on proinflammatory cytokine production and Ras-mediated cell activation. 1612 92

Modern therapeutic methods for manipulation of gene expression in allergic diseases have been receiving increased attention in the emerging era of functional genomics. With the growing application of gene silencing technologies, pharmacological modulation of translation represents a great advance in molecular therapy for allergy. Several strategies for sequence-specific post-transcriptional inhibition of gene expression can be distinguished: antisense oligonucleotides (AS-ONs), ribozymes (RZs), DNA enzymes (DNAzymes), and RNA interference (RNAi) triggered by small interfering RNAs (siRNAs). Potential anti-mRNA drugs in asthma and other allergic disorders may be targeted to cell surface receptors (adenosine A1 receptor, high-affinity receptor Fc-epsilon RI-alpha, cytokine receptors), adhesion molecules and ligands (ICAM-1, VLA-4), ion channels (calcium-dependent chloride channel-1), cytokines and related factors (IL-4, IL-5, IL-13, SCF, TNF-alpha, TGF-beta1), intracellular signal transduction molecules, such as tyrosine-protein kinases (Syk, Lyn, Btk), serine/ threonine-protein kinases (p38 alpha MAPkinase, Raf-1), non-kinase signaling proteins (RasGRP4), and transcription factors involved in Th2 differentiation and allergic inflammation (STAT-6, GATA-3, NF-kappaB). The challenge to scientists is to determine which of the candidate targets warrants investment of time and resources. New-generation respirable AS-ONs, external guide sequence ribozymes, and RNA interference-based therapies have the potential to satisfy unmet needs in allergy treatment, acting at a more proximal level to a key etiopathogenetic molecular process, represented by abnormal expression of genes. Moreover, antisense and siRNA technologies imply a more rational design of new drugs for allergy.
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PMID:Antisense- and RNA interference-based therapeutic strategies in allergy. 1636 94

Adhesion of mononuclear cells to the vascular endothelium and their subsequent transmigration into the arterial wall represent key events in the pathogenesis of arteriosclerosis. In previous studies we have shown that high density lipoproteins (HDL) and the HDL-associated sphingosylphosphorylcholine (SPC) have the ability to suppress the TNF-alpha-induced expression of endothelial cell E-selectin. However, the current understanding of the mechanism by which HDL reduces the expression of E-selectin is still incomplete. In the present study we show that interaction of the HDL-associated sphingosylphosphorylcholine and sphingosylgalactosyl-3-sulfate (lysosulfatide, LSF) with the G-protein-coupled EDG receptor initiates a signalling cascade that activates the protein kinase Akt and reduces the E-selectin, ICAM-1 and VCAM-1 expression on protein and mRNA level. This signalling cascade is consistently associated with a reduced translocation of TNF-alpha-activated NF-kappaB into the cell nucleus. The suppressor effect of SPC and LSF is completely reverted by inhibition of the phosphatidylinositol- 3-kinase/Akt pathway. We conclude that the antiatherogenic/antiinflammatory effect of lysosphingolipids depends on a competitive interaction of EDG receptor-induced inhibition and TNF-alpha-initiated stimulation of NF-kappaB translocation into the cell nucleus thereby preventing or stimulating inflammatory events in atherogenesis.
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PMID:The antiatherogenic and antiinflammatory effect of HDL-associated lysosphingolipids operates via Akt -->NF-kappaB signalling pathways in human vascular endothelial cells. 1645 77

Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, is known to induce the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40 and CD40 ligand (CD40L) on monocytes, the production of interferon (IFN)-gamma and IL-12 and the proliferation of lymphocytes during the human mixed lymphocyte reaction (MLR). Ciprofloxacin (CIP), which is useful for the clinical treatment of infections due to its antibacterial properties after transplantation, was shown to suppress the IFN-gamma and IL-12 production, the lymphocyte proliferation and the ICAM-1, B7.1, B7.2 and CD40 expression on monocytes during MLR in the presence of IL-18. CIP also induced the production of prostaglandin (PG) E2. In order to determine whether the effects of CIP on the expression of the activation markers were due to CIP-dependent production of PGE2, we examined the effect of cyclooxygenase (COX)-2 and protein kinase A (PKA) inhibitors on the actions of CIP. Thereby, the inhibitors were found to abolish the actions of CIP. These results therefore suggest that CIP might exert its immune modulatory effects via the production of PGE2.
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PMID:The immunosuppressive effects of ciprofloxacin during human mixed lymphocyte reaction. 1645 73

A20 is a NF-kappaB-dependent gene that has dual anti-inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti-inflammatory function via blockade of NF-kappaB and NF-kappaB-dependent proteins ICAM-1 and MCP-1. A20 inhibits SMC proliferation via increased expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Surprisingly, A20 sensitizes SMC to cytokine- and Fas-mediated apoptosis through a novel NO-dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re-endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined anti-inflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20-based therapies hold promise for the prevention and treatment of neointimal disease.
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PMID:A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia. 1681 17

Nicotine is thought to inhibit the production of proinflammatory cytokines from macrophages through an anti-inflammatory pathway that is dependent on nicotinic acetylcholine receptor alpha7 subunit (alpha7-nAChR). IL-18, an important proinflammatory cytokine, is reported to induce the expression of adhesion molecules on monocytes, thus enhancing cell-to-cell interactions with T-cells and contributing to IL-18-initiated cytokine production. Accordingly, inhibition of IL-18 suppresses systemic inflammatory responses. In the present study, we found that nicotine inhibited the IL-18-enhanced expression of ICAM-1, B7.2, and CD40 on monocytes, and the production of IL-12, IFN-gamma, and TNF-alpha by PBMC. A nonselective and a selective alpha7-nAChR antagonist, mecamylamine, and alpha-bungarotoxin abolished the effects of nicotine, suggesting that this depends on alpha7-nAChR stimulation. It is reported that nicotine induces prostaglandinE2 (PGE(2)) production in PBMC through the up-regulation of cyclooxygenase (COX)-2 expression. PGE(2) is known to activate the EP2/EP4-receptor, leading to an increase in cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity. Consistent with this, we found that COX-2 and PKA inhibitors prevented the effects of nicotine on adhesion molecule expression and cytokine production, indicating that the mechanism of action of nicotine may be via endogenous PGE(2) production.
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PMID:Effect of nicotine on IL-18-initiated immune response in human monocytes. 1696 84

Cell-to-cell interaction through binding intercellular adhesion molecule (ICAM)-1, B7.1, B7.2 and CD40 on monocytes and their ligands on T-cells plays roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, induces the expression of ICAM-1, B7.1, B7.2 and CD40, production of interferon (IFN)-gamma and IL-12 and proliferation of lymphocytes during human mixed lymphocyte reaction. Nicotine is known to inhibit the production of pro-inflammatory cytokines from macrophages through the stimulation of nicotinic acetylcholine receptor alpha7 subunit. In the present study, we examined the effect of increasing concentrations ranging from 0.1 to 100 microM of nicotine on the expression of ICAM-1, B7.1, B7.2 and CD40, production of IFN-gamma and IL-12 and proliferation of lymphocytes during mixed lymphocyte reaction treated with IL-18 at 100 ng/ml for 48 h. Nicotine inhibited the expression of adhesion molecules, cytokine production and lymphocyte proliferation. The IC50 values of nicotine for inhibition of the IL-18-enhanced ICAM-1 expression, IFN-gamma production and proliferation were 1, 1 and 2 microM, respectively. A non-selective and a selective antagonist for nicotinic acetylcholine receptor alpha7 subunit, mecamylamine and alpha-bungarotoxin abolished the effects of nicotine. The actions of nicotine might depend on stimulation of nicotinic acetylcholine receptor alpha7 subunit. Nicotine induced prostaglandin E(2) production during mixed lymphocyte reaction. The inhibitors of cyclooxygenase (COX)-2 and protein kinase A (PKA) at 100 microM inhibited the actions of nicotine, suggesting that the endogenous prostaglandin E(2) might be, at least, partially involved the actions of nicotine.
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PMID:The immunosuppressive effects of nicotine during human mixed lymphocyte reaction. 1725 63

The cell-to-cell interaction through binding of intercellular adhesion molecule (ICAM)-1 on monocytes to their ligands lymphocyte function-associated antigen (LFA)-1 on T-cells plays important roles in cytokine production and T-cell proliferation. Interleukin (IL)-18, which plasma levels are elevated in patients during acute rejection following organ transplantation, induces the expression of ICAM-1 on monocytes, production of interferon (IFN)-gamma and IL-12 and lymphocyte proliferation during human mixed lymphocyte reaction. Activation of the adenosine A(2A) receptor on during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In the present study, we examined the effect of adenosine at increasing concentrations ranging from 0.1 to 100 microM on the IL-18-enhanced expression of ICAM-1, production of IFN-gamma and IL-12 and lymphocyte proliferation during human mixed lymphocyte reaction. Adenosine inhibited the IL-18-initiated immune responses. The IC(50) values of adenosine for inhibition of the IL-18-enhanced ICAM-1 expression, IFN-gamma production and lymphocyte proliferation were 20 microM, respectively. The actions of adenosine depended on the stimulation of adenosine A(2A) receptor. An inhibitor of protein kinase A (PKA) at 100 microM inhibited the actions of adenosine, suggesting that PKA might be involved in the actions of adenosine. On the other hand, the stimulation of adenosine A(1) and A(3) receptor blocked the actions of adenosine A(2A) receptor stimulation. These results suggest that adenosine inhibits the immune responses during mixed lymphocyte reaction via adenosine A(2A) receptor.
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PMID:Effect of adenosine receptor subtypes stimulation on mixed lymphocyte reaction. 1737 32

We examined the immunological actions of Sophy beta-glucan(Ikewaki N., et al. United States Patent 6956120 and Japan Patent 2004-329077), a type of beta-1,3-1,6 glucan produced by the black yeast Aureobasidium pullulans (A. pullulans) strain AFO-202, currently available commercially as a health food supplement, using different human in vitro experimental systems. Sophy beta-glucan significantly (P<0.01) stimulated the (3)H-thymidine incorporation rates (marker of DNA synthesis) in human peripheral blood mononuclear cells (PBMCs) obtained from normal adult donors, in vitro. Enzyme-linked immunoassays (EIAs) revealed that Sophy beta-glucan stimulated the production of interleukin-8 (IL-8) or soluble Fas (sFas), but not that of IL-1beta, IL-2, IL-6, IL-12 (p70+40), interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) or soluble Fas ligand (sFasL), in either cultured PBMCs or cells of the human monocyte-like cell line, U937. The induction by Sophy beta-glucan of DNA synthesis in PBMCs was completely blocked by the addition of monoclonal antibodies (mAbs) to CD11a, CD54, human leukocyte antigen-class II (HLA-class II), Toll-like receptor-2 (TLR-2), and Toll-like receptor-4 (TLR-4). In these blocking experiments using the mAbs, the main differences in the results between PBMCs and U937 cells were that the mAbs against TLR-2 and TLR-4 did not block the Sophy beta-glucan-induced production of IL-8 in the U937 cells. Furthermore, a mAb to the beta-glucan receptor, Dectin-1, significantly (P<0.05) blocked the Sophy beta-glucan induced DNA synthesis in the PBMCs, and Sophy beta-glucan-induced production of IL-8 in the U937 cells. The Sophy beta-glucan-induced production of IL-8 in the U937 cells was significantly (P<0.01) blocked by the conventional protein kinase C (PKC) inhibitor Go6976, the novel PKC inhibitor Rottlerin, the protein kinase A (PKA) inhibitor H-89, and the protein tyrosine kinase (PTK) inhibitor herbimycin A. Among these, the blocking effect of the novel PKC (PKC delta isoenzyme) inhibitor Rottlerin was the most pronounced. Studies employing reverse transcriptase-polymerase chain reaction (RT-PCR) showed that Sophy beta-glucan stimulated the expression of IL-8 mRNA in the U937 cells, and that this induction was inhibited by Rottlerin. Sophy beta-glucan also blocked the stimulator cell induction of DNA synthesis and IFN-gamma production in the responder cells in a one-way mixed lymphocyte reaction (MLR) using allogenic PBMCs. Interestingly, immunoglobulin G (IgG), but not IgM to Sophy beta-glucan was detected in the sera derived from normal adult donors and from the umbilical cord blood of neonates. Taken together, these findings strongly suggest that the Sophy beta-glucan may have unique immune regulatory or enhancing properties that could be exploited by the health food, medical and pharmaceutical industries.
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PMID:Immunological actions of Sophy beta-glucan (beta-1,3-1,6 glucan), currently available commercially as a health food supplement. 1789 3

We studied the effect of leukotriene D(4) (LTD(4)) on a human bronchial epithelial cell line (16HBE) overexpressing the cysteinyl leukotriene (CysLT) (1) receptor (HBECysLT(1)R), looking at the associated signal transduction mechanisms as well as at effects on inflammatory cell adhesion. The results obtained showed that LTD(4) increases the phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 and of the signal transducer and activator of transcription 1 (STAT-1) in serine 727 (STAT-1Ser727), resulting in increased eosinophil adhesion to HBECysLT(1)R, associated with enhanced surface expression of intercellular adhesion molecule (ICAM) 1. Pretreatment with a CysLT(1)R-selective antagonist or with a selective inhibitor of protein kinase C (PKC) or with a selective inhibitor of the mitogen-activated protein kinase kinase (MEK) successfully suppressed both LTD(4)-induced STAT-1Ser727 phosphorylation and the associated increase in eosinophil adhesion. The use of the MEK inhibitor and of the selective CysLT(1)R antagonist in electrophoretic mobility shift assay experiments showed that LTD(4) promotes the nuclear translocation of STAT-1 through the activation of ERK1/2 pathway. The key role of STAT-1 in leukotriene D(4) transduction signaling was confirmed by RNA interference experiments, where silencing of STAT-1 expression abolished the effect of leukotriene D(4) on eosinophil adhesion. In conclusion, for the first time, we provide evidence of the involvement of STAT-1 in the signal transduction mechanism of the CysLT(1) receptor; phosphorylation of STAT-1, through PKC and ERK1/2 activation, causes enhanced ICAM-1 surface expression and eosinophil adhesion. Effective CysLT(1)R antagonism may therefore contribute to the control of the chronic inflammatory condition that characterizes human airways in asthma.
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PMID:Cysteinyl leukotriene-1 receptor activation in a human bronchial epithelial cell line leads to signal transducer and activator of transcription 1-mediated eosinophil adhesion. 1830 14


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