title: P38 MAPK: critical molecule in thrombin-induced NF-kappa B-dependent leukocyte recruitment.
abstract: Thrombin-stimulated endothelium synthesizes numerous adhesion molecules to recruit leukocytes; however, it is unknown which intracellular pathways are responsible for this event. A recent report from our laboratory has shown that thrombin induces E-selectin expression and that blocking nuclear factor-kappa B (NF-kappa B) activity partially blocked both E-selectin expression (60%) and leukocyte recruitment. In this study, we systematically assessed the importance of p38 MAPK in thrombin-induced NF-kappa B activation and E-selectin-dependent leukocyte recruitment. Thrombin caused phosphorylation of p38 MAPK, its substrate ATF-2, and JNK MAPK, but not ERK MAPK. The p38 MAPK inhibitors, SKF86002 and SB-203580 only reduced ATF-2 activity. We treated human umbilical vein endothelial cells with SKF86002, 1 h before thrombin stimulation, and noted inhibition of NF-kappa B mobilization and complete inhibition of leukocyte rolling and adhesion in a laminar flow chamber. Significant inhibition of leukocyte recruitment and E-selectin expression was also observed with SB-203580. SKF86002 did not affect other systems, including tumor necrosis factor-alpha-induced E-selectin-dependent leukocyte recruitment. Moreover, thrombin-induced rapid mobilization of P-selectin from Weibel Palade bodies was not p38 MAPK dependent. These data suggest that thrombin induces p38 MAPK activation, which leads to NF-kappa B mobilization to the nucleus and causes the upregulation of E-selectin and subsequent leukocyte recruitment.
authors.affiliation: Immunology Research Group, Department of Physiology, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Jaswinder
authors.initials: J
authors.lastname: Kaur
authors.forename: Richard C
authors.initials: RC
authors.lastname: Woodman
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D001667:Binding, Competitive; D002448:Cell Adhesion; D002478:Cells, Cultured; D019040:E-Selectin / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D019007:P-Selectin / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology*; D014471:Umbilical Veins; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D019040:E-Selectin; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016328:NF-kappa B; D019007:P-Selectin; D011725:Pyridines; D013844:Thiazoles; D000255:Adenosine Triphosphate; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013917:Thrombin; C093642:SB 203580