We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
A specific p47<sup>phox</sup>-serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites.
- Authors
Pham My-Chan Dang; Stensballe, Allan; Boussetta, Tarek; Raad, Houssam; Dewas, Cedric; Kroviarski, Yolande; Hayem, Gilles; Jensen, Ole N.; Gougerot-Pocidalo, Marie-Anne; El-Benna, Jamel
- Abstract
Neutrophil NADPH oxidase plays a key role in host defense and in inflammation by releasing large amounts of superoxide and other ROSs. Proinflammatory cytokines such as GM-CSF and TNF-α prime ROS production by neutrophils through unknown mechanisms. Here we used peptide sequencing by tandem mass spectrometry to show that GM-CSF and TNF-α induce phosphorylation of Ser345 on p47phox, a cytosolic component of NADPH oxidase, in human neutrophils. As Ser345 is located in the MAPK consensus sequence, we tested the effects of MAPK inhibitors. Inhibitors of the ERK1/2 pathway abrogated GM-CSF-induced phosphorylation of Ser345, while p38 MAPK inhibitor abrogated TNF-α-induced phosphorylation of Ser345. Transfection of HL 60 cells with a mutated p47phox (S345A) inhibited GM-CSF- and TNF-α-induced priming of ROS production. This event was also inhibited in neutrophils by a cell-permeable peptide containing a TAT-p47phox-Ser345 sequence. Furthermore, ROS generation, p47phox-Ser345 phosphorylation, and ERK1/2 and p38 MAPK phosphorylation were increased in synovial neutrophils from rheumatoid arthritis (RA) patients, and TAT Ser345 peptide inhibited ROS production by these primed neutrophils. This study therefore identifies convergent MAPK pathways on Ser345 that are involved in GM-CSF- and TNF-a-induced priming of neutrophils and are activated in RA. Inhibition of the point of convergence of these pathways might serve as a novel antiinflammatory strategy.
- Publication
Journal of Clinical Investigation, 2006, Vol 116, Issue 7, p2033
- ISSN
0021-9738
- Publication type
Academic Journal
- DOI
10.1172/JCI27544