首页 | 本学科首页   官方微博 | 高级检索  
   检索      


TNF-induced beta2 integrin activation involves Src kinases and a redox-regulated activation of p38 MAPK
Authors:Bouaouina Mohamed  Blouin Eric  Halbwachs-Mecarelli Lise  Lesavre Philippe  Rieu Philippe
Institution:Institut National de la Santé et de la Recherche Médicale U507, Necker Hospital, Paris, France.
Abstract:We previously demonstrated that the TNF-alpha-induced inside-out signaling leading to beta(2) integrin activation is redox regulated. To identify kinases involved in this pathway, the effects of kinase inhibitors on the expression of beta(2) integrin activation neoepitope (clone 24) were investigated. We show that both p38 MAPK (inhibited by SB203580) and Src kinases (inhibited by PP2) are involved in beta(2) integrin activation by TNF and oxidants in human neutrophils. Src kinases appeared constitutively active in resting neutrophils and not further activated by TNF or oxidants in nonadherent conditions. However, PP2 blocked both TNF-induced expression of the 24 epitope and cell adhesion promoted by the integrin activating anti-CD18 KIM185 mAb, showing that both the inside-out and the outside-in signaling involve Src kinases. p38 MAPK was activated by TNF and oxidants in nonadherent conditions i.e., with 10 mM EDTA. This activation in EDTA resulted in CD11b, CD35 and CD66 up-regulation and in an oxidative response, all blocked by SB203580 and PP2. p38 MAPK was not activated upon direct integrin activation by KIM185 mAb. Thus, p38 activation allows the study to distinguish the initial transduction pathway leading to beta(2) integrin activation from the signaling resulting from integrin engagement. Finally, p38 MAPK activation by TNF was blocked by diphenylene iodonium, an inhibitor of flavoprotein oxidoreductase, and by the free radical scavenger N-acetylcystein. Taken together, these results demonstrate, for the first time, that constitutively activated Src tyrosine kinases and a redox-regulated activation of p38 MAPK are involved in TNF inside-out signaling leading to beta(2) integrin activation.
Keywords:
本文献已被 PubMed 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号