Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 202, Issue 3, Pages 353-361Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20050778
Keywords
-
Categories
Funding
- NHLBI NIH HHS [R01 HL046849, R01 HL064774, HL46849, HL64774, R37 HL064774] Funding Source: Medline
- NIAID NIH HHS [AI46382, R01 AI046382] Funding Source: Medline
- NICHD NIH HHS [HD42060, R01 HD038722, HD38722] Funding Source: Medline
- NIGMS NIH HHS [R01 GM062328, GM62328] Funding Source: Medline
Ask authors/readers for more resources
Through chemical screening, we identified a pyrazolone that reversibly blocked the activation of phagocyte oxidase (phox) in human neutrophils in response to tumor necrosis factor (TNF) or formylated peptide. The pyrazolone spared activation of phox by phorbol ester or bacteria, bacterial killing, TNF-induced granule exocytosis and phox assembly, and endothelial transmigration. We traced the pyrazolone's mechanism of action to inhibition of TNF-induced intracellular Ca2+ elevations, and identified a nontransmembrane (soluble) adenylyl cyclase (sAC) in neutrophils as a Ca2+-sensing source of cAMP. A sAC inhibitor mimicked the pyrazolone's effect on phox. Both compounds blocked TNF-induced activation of Rap1A, a phox-associated guanosine triphosphatase that is regulated by cAMP. Thus, TNF turns on phox through a Ca2+-triggered, sAC-dependent process that may involve activation of Rap1A. This pathway may offer opportunities to suppress oxidative damage during inflammation without blocking antimicrobial function.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available