Concentration dependent dual effect of thrombin in endothelial cells via Par-1 and Pi3 Kinase.
Disruption of endothelial barrier is a critical pathophysiological factor in inflammation. Thrombin exerts a variety of cellular effects including inflammation and apoptosis through activation of the protease activated receptors (PARs). The activation of PAR-1 by thrombin is known to have a bimodal effect in endothelial cell permeability with a low concentration (pM levels) eliciting a barrier protective and a high concentration (nM levels) eliciting a barrier disruptive response. It is not known whether this PAR-1-dependent activity of thrombin is a unique phenomenon specific for the in vitro assay or it is part of a general anti-inflammatory effect of low concentrations of thrombin that may have a physiological relevance. Here, we report that low concentrations of thrombin or of PAR-1 agonist peptide induced significant anti-inflammatory activities. However, relatively high concentration of thrombin or of PAR-1 agonist peptide showed pro-inflammatory activities. By using function-blocking anti-PAR-1 antibodies and PI3 kinase inhibitor, we show that the direct anti-inflammatory effects of low concentrations of thrombin are dependent on the activation of PAR-1 and PI3 kinase. These results suggest a role for cross communication between PAR-1 activation and PI3 kinase pathway in mediating the cytoprotective effects of low concentrations of thrombin in the cytokine-stimulated endothelial cells. J. Cell. Physiol. 219: 744-751, 2009. (c) 2009 Wiley-Liss, Inc.
Bae
Jong-Sup
JS
Department of Herbal Pharmaceutical Engineering, College of Herbal Bio-Industry, Daegu Haany University, Gyeongsan, Republic of Korea. BaeJS@dhu.ac.kr
Kim
Yong-Ung
YU
Park
Moon-Ki
MK
Rezaie
Alireza R
AR
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects; D009842:Oligopeptides / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism*; D013917:Thrombin / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D009842:Oligopeptides; D044463:Receptor, PAR-1; D014409:Tumor Necrosis Factor-alpha; C508781:threonyl-phenylalanyl-leucyl-leucyl-arginyl-asparagine; D019869:Phosphatidylinositol 3-Kinases; D013917:Thrombin