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B-Dependent Leukocyte Recruitment
1 Department of Physiology & Biophysics/Medicine, University of Calgary, Calgary, AB, Canada
* To whom correspondence should be addressed. E-mail: pkubes{at}ucalgary.ca.
Thrombin-stimulated endothelium synthesizes numerous adhesion molecules to recruit leukocytes, however, it is presently unknown which intracellular pathways are responsible for this event. A recent report from our laboratory has shown that thrombin induces E-selectin expression and blocking NF
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 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 SB203580 only reduced ATF-2 activity. We treated HUVEC with SKF86002, 1 h prior to 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 SB203580. SKF86002 did not affect other systems including TNF
-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 NFB mobilization to the nucleus and causes the upregulation of E-selectin and subsequent leukocyte recruitment.
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