Document Detail

TNF-induced beta2 integrin activation involves Src kinases and a redox-regulated activation of p38 MAPK.
MedLine Citation:
PMID:  15240725     Owner:  NLM     Status:  MEDLINE    
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.
Mohamed Bouaouina; Eric Blouin; Lise Halbwachs-Mecarelli; Philippe Lesavre; Philippe Rieu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  173     ISSN:  0022-1767     ISO Abbreviation:  J. Immunol.     Publication Date:  2004 Jul 
Date Detail:
Created Date:  2004-07-08     Completed Date:  2004-08-27     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1313-20     Citation Subset:  AIM; IM    
Institut National de la Santé et de la Recherche Médicale U507, Necker Hospital, Paris, France.
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MeSH Terms
Antigens, CD18 / metabolism*
Mitogen-Activated Protein Kinases / metabolism*
Neutrophils / metabolism
Signal Transduction / physiology
Tumor Necrosis Factor-alpha / metabolism*
p38 Mitogen-Activated Protein Kinases
src-Family Kinases / metabolism*
Reg. No./Substance:
0/Antigens, CD18; 0/Tumor Necrosis Factor-alpha; EC Kinases; EC Protein Kinases; EC Mitogen-Activated Protein Kinases

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