Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased levels of isoprostanes have been detected in human atherosclerotic lesions. To examine a possible role for 8-iso-prostaglandin E(2) (8-iso-PGE(2)) in atherogenesis, we tested the effect of 8-iso-PGE(2) on adhesion of leukocytes to human umbilical vein endothelial cells (EC). We demonstrate that 8-iso-PGE(2) stimulates EC to bind monocytes, but not neutrophils. This effect was inhibited by the thromboxane A(2) receptor antagonist SQ29548. Moreover, 8-iso-PGE(2) increased levels of cyclic AMP in EC, and monocyte adhesion induced by 8-iso-PGE(2) was blocked by a protein kinase A inhibitor, H89. In addition, 8-iso-PGE(2 )induced phosphorylation of p38 and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein (MAP) kinase and stimulated expression of EGR-1. A specific inhibitor of p38 MAP kinase (SB203580) abrogated monocyte binding, whereas an inhibitor of the ERK pathway (PD98059) did not block monocyte adhesion induced by 8-iso-PGE(2). Activation of nuclear factor-kappaB (NF-kappaB) and expression of NFkappaB-dependent genes intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin were not induced by 8-iso-PGE(2). Taken together, these results demonstrate that 8-iso-PGE(2) stimulates EC to specifically bind monocytes, but not neutrophils. This effect is mediated by cyclic AMP/protein kinase A- and p38 MAP kinase-dependent pathways and is independent of the classical inflammatory NFkappaB pathway. Thus, formation of 8-iso-PGE(2) may play an important role in chronic inflammatory diseases such as atherosclerosis by increasing adhesion and extravasation of monocytes.
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PMID:The isoprostane 8-iso-PGE2 stimulates endothelial cells to bind monocytes via cyclic AMP- and p38 MAP kinase-dependent signaling pathways. 1271 76

The alpha 4/beta 1 integrin very late antigen-4 (CD49d/CD29) is up-regulated on circulating neutrophils of septic patients. Although no individual agent mimics this effect of sepsis, we now report that following priming of human neutrophils with lipopolysaccharide or tumor necrosis factor alpha (TNF-alpha), addition of formyl-Met-Leu-Phe (fMLP) results in a "stimulated", sepsis-like, four- to fivefold rise in CD49d expression. TNF/fMLP stimulation also produced a similar increase in CD49d-mediated adhesion of neutrophils to a vascular cell adhesion molecule-1 (VCAM-1)-coated surface. Adenosine is a naturally occurring, anti-inflammatory mediator released from injured or inflamed tissues. We observed that stimulated neutrophil CD49d expression was decreased by activation of A(2A) adenosine receptors (A(2A)AR) with the selective agonist 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylicacid methyl ester (ATL146e; EC(50)=6.4 nM). ATL146e (100 nM) also reduced the fraction of stimulated neutrophils that adhered to VCAM-1 from 38 +/- 6% to 27 +/- 5%. Inhibition of CD49d expression was equally inhibited by ATL146e, added before or after TNF priming, and was reversed by incubation with the A(2A)AR-selective antagonist 4-[2-[7-amino-2-(2-furyl) (1, 2, 4)triazolo(2,3-a) (1, 3, 5)triazin-5-yl-amino]ethyl]-phenol (ZM241385; 100 nM). A suboptimal ATL146e concentration (1 nM) combined with the type IV phosphodiesterase inhibitor rolipram (100 nM) synergistically decreased stimulated CD49d expression by >50%. The cyclic adenosine monophosphate (cAMP)-dependent kinase [protein kinase A (PKA)] inhibitor H-89 (10 microM) reversed the effect of ATL146e on stimulated CD49d expression. Other means of increasing cAMP in neutrophils also decreased stimulated CD49d expression. We conclude that adenosine binding to A(2A)AR counteracts stimulation of neutrophil CD49d integrin expression and neutrophil binding to VCAM-1 via a cAMP/PKA-mediated pathway.
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PMID:Activation of A2A adenosine receptors inhibits expression of alpha 4/beta 1 integrin (very late antigen-4) on stimulated human neutrophils. 1452 68

Nitric oxide (NO) exerts both antiatherogenic and proatherogenic effects, but the cellular and molecular mechanisms that contribute to modulation of atherosclerosis by NO are not understood completely. The cGMP-dependent protein kinase I (cGKI) is a potential mediator of NO signaling in vascular smooth muscle cells (SMCs). Postnatal ablation of cGKI selectively in the SMCs of mice reduced atherosclerotic lesion area, demonstrating that smooth muscle cGKI promotes atherogenesis. Cell-fate mapping indicated that cGKI is involved in the development of SMC-derived plaque cells. Activation of endogenous cGKI in primary aortic SMCs resulted in cells with increased levels of proliferation; increased levels of vascular cell adhesion molecule-1, peroxisome proliferator-activated receptor gamma, and phosphatidylinositol 3-kinase/Akt signaling; and decreased plasminogen activator inhibitor 1 mRNA, which all are potentially proatherogenic properties. Taken together, these results highlight the pathophysiologic significance of vascular SMCs in atherogenesis and identify a key role for cGKI in the development of atherogenic SMCs in vitro and in vivo. We suggest that activation of smooth muscle cGKI contributes to the proatherogenic effect of NO and that inhibition of cGKI might be a therapeutic option for treating atherosclerosis in humans.
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PMID:A proatherogenic role for cGMP-dependent protein kinase in vascular smooth muscle cells. 1459 16

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

We found previously that immunosuppressive macrophages (Mphis) induced by Mycobacterium intracellulare infection (MI-Mphis) transmitted their suppressor signals to target T cells through cell contact with target T cells. In this study, we examined what kinds of Mphi surface molecules are required for such cell-to-cell interaction. First, it was found that a B7-1-like molecule (B7-1LM) recognizable with one of three test clones of anti-B7-1 monoclonal antibodies (mAbs) was required for expression of the Mphi suppressor activity. Neither anti-B7-2, anti-ICAM-1, nor anti-VCAM-1 mAb blocked the Mphi suppressor activity. Second, MI-Mphis increased the expression of B7-1LM in parallel with the acquisition of the suppressor activity. Moreover, MI-Mphis bound with target T cells in a B7-1LM-dependent fashion. Third, mAb blocking of CTLA-4 on target T cells did not reduce the suppressor activity of MI-Mphis, suggesting the role of a putative molecule on target T cells other than CTLA-4 as the receptor for B7-1LM of MI-Mphis. Fourth, concanavalin A (Con A) stimulation of MI-Mphis was needed for effective cell contact with target T cells and subsequent expression of the suppressor activity of MI-Mphis. Fifth, the Con A-induced increase in the suppressor activity of MI-Mphis was inhibited by KN-62 but not by herbimycin A, H-7, nor H-88, indicating that Con A-induced up-regulation of MI-Mphi function is mediated by calmodulin-dependent protein kinase II or ATP/P2Z receptors, but independent of protein tyrosine kinase, protein kinase C, and protein kinase A. These findings indicate that a B7/CTLA-4-independent mechanism is needed for the transmission of the suppressor signals from MI-Mphis to target T cells.
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PMID:The role of B7 molecules in the cell contact-mediated suppression of T cell mitogenesis by immunosuppressive macrophages induced with mycobacterial infection. 1500 68

We recently reported that CD47 (integrin-associated protein) on sickle red blood cells (SS RBCs) activates G-protein-dependent signaling, which promotes cell adhesion to immobilized thrombospondin (TSP) under relevant shear stress. These data suggested that signal transduction in SS RBCs may contribute to the vaso-occlusive pathology observed in sickle cell disease. However, the CD47-activated SS RBC adhesion receptor(s) that mediated adhesion to immobilized TSP remained unknown. Here we demonstrate that the alpha4beta1 integrin (VLA-4) is the receptor that mediates CD47-stimulated SS RBC adhesion to immobilized TSP. This adhesion requires both the N-terminal heparin-binding domain and the RGD site of TSP. CD47 signaling induces an "inside-out" activation of alpha4beta1 on SS RBCs as indicated by an RGD-dependent interaction of this integrin with soluble, plasma fibronectin. However, CD47 engagement also induces an alpha4beta1-mediated, RGD-independent adhesion of SS RBCs to immobilized vascular cell adhesion molecule-1 (VCAM-1). CD47 signaling in SS RBCs appears to be independent of large scale changes in cAMP formation but nonetheless promotes alpha4beta1-mediated adhesion via a protein kinase A-dependent, serine phosphorylation of the alpha4 cytoplasmic domain. CD47-activated SS RBC adhesion absolutely requires the Src family tyrosine kinases and is also enhanced by treatment of SS RBCs with low concentrations of cytochalasin D, which may release alpha4beta1 from cytoskeletal restraints. In addition, CD47 co-immunoprecipitates with alpha4beta1 in a sickle reticulocyte-enriched fraction of SS RBCs. These studies therefore identify the alpha4beta1 integrin on SS RBCs as a CD47-activated receptor for TSP, VCAM-1, and plasma fibronectin, revealing novel binding characteristics of this integrin.
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PMID:Mechanism of CD47-induced alpha4beta1 integrin activation and adhesion in sickle reticulocytes. 1529 85

Adrenomedullin (AM), a potent vasodilator peptide, has recently been suggested to function as an endogenous antioxidant. However, its potential site of action at the cellular level has not been clarified. The present study was undertaken to investigate whether AM directly inhibits intracellular reactive oxygen species (ROS) generation and redox-sensitive gene expression stimulated by angiotensin (Ang) II in rat aortic endothelial cells (ECs). Ang II (10(-7) mol/l) significantly increased intracellular ROS levels in ECs as measured by dichlorofluorescein (DCF) fluorescence. AM inhibited Ang II-stimulated ROS generation in a dose-dependent manner and this effect was abolished by a superoxide radical scavenger, NAD(P)H oxidase inhibitor, and a protein kinase A (PKA) inhibitor, and mimicked by a cell-permeable cAMP analog. A real-time reverse transcription-polymerase chain reaction (RT-PCR) study showed that Ang II significantly upregulated a set of redox-sensitive genes (ICAM-1, VCAM-1, PAI-1, tissue factor, MCP-1, osteopontin), and these effects were blocked by an antioxidant, N-acetyl cysteine (NAC). AM similarly and dose-dependently inhibited the Ang II-induced upregulation of the entire set of these genes via a receptor-mediated and PKA-dependent pathway, and the degrees of inhibition were similar to those by NAC. In conclusion, the present study demonstrated that AM potently blocked the Ang II-stimulated intracellular ROS generation from NAD(P)H oxidase and the subsequent redox-sensitive gene expression via a cAMP-dependent mechanism in ECs, suggesting that AM has vasculoprotective effects against pro-oxidant stimuli.
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PMID:Adrenomedullin inhibits angiotensin II-induced oxidative stress and gene expression in rat endothelial cells. 1602 44

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

Leukocyte transmigration can be affected by shear stress; however, the mechanisms by which shear stress modulates transmigration are unknown. We found that adhesion of eosinophils or an eosinophilic cell line to intereukin 4-stimulated endothelial cells led to a shear-dependent increase in endothelial cell intracellular calcium and increased phosphorylation of extracellular signal-regulated kinase (ERK) 2, but not c-Jun NH2-terminal kinase or p38 mitogen-activated protein kinase. Latex beads coated with antibodies were used to characterize the role of specific endothelial cell surface molecules in initiating signaling under shear conditions. We found that ligation of either vascular cell adhesion molecule-1 or E-selectin, but not major histocompatibility complex class I, induced a shear-dependent increase in ERK2 phosphorylation in cytokine-stimulated endothelial cells. Disassembly of the actin cytoskeleton with latrunculin A prevented ERK2 phosphorylation after adhesion under flow conditions, supporting a role for the cytoskeleton in mechano-sensing. Rapid phosphorylation of focal adhesion kinase and paxillin occurred under identical conditions, suggesting that focal adhesions were also involved in mechanotransduction. Finally, we found that Rho-associated protein kinase and calpain were both critical in the subsequent transendothelial migration of eosinophils under flow conditions. These data suggest that ligation of leukocyte adhesion molecules under flow conditions leads to mechanotransduction in endothelial cells, which can regulate subsequent leukocyte trafficking.
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PMID:Eosinophil adhesion under flow conditions activates mechanosensitive signaling pathways in human endothelial cells. 1617 63

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


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