P38 MAPK: critical molecule in thrombin-induced NF- B-dependent leukocyte recruitment

Kaur, Jaswinder, Richard C. Woodman, and Paul Kubes. P38 MAPK: critical molecule in thrombin-induced NFB-dependent leukocyte recruitment. Am J Physiol Heart Circ Physiol 284: H1095–H1103, 2003. First published December 27, 2002; 10.1152/ajpheart.00016.2002.—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 factorB (NFB) 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 NFB 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 NFB 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-induced E-selectin-dependent leukocyte recruitment. Moreover, thrombininduced 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 NFB mobilization to the nucleus and causes the upregulation of E-selectin and subsequent leukocyte recruitment.