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

被引:39
作者
Kaur, J [1 ]
Woodman, RC [1 ]
Kubes, P [1 ]
机构
[1] Univ Calgary, Hlth Sci Ctr, Dept Physiol & Biophys, Immunol Res Grp, Calgary, AB T2N 4N1, Canada
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 2003年 / 284卷 / 04期
关键词
endothelium; selectins; inflammation;
D O I
10.1152/ajpheart.00016.2002
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-kappaB (NF-kappaB) 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-kappaB 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, I h before thrombin stimulation, and noted inhibition of NF-kappaB 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-kappaB mobilization to the nucleus and causes the upregulation of E-selectin and subsequent leukocyte recruitment.
引用
收藏
页码:H1095 / H1103
页数:9
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