Calcium-sensing soluble adenylyl cyclase mediates TNF signal transduction in human neutrophils

Hyunsil Han, Alexander Stessin, Julia Roberts, Kenneth Hess, Narinder Gautam, Margarita Kamenetsky, Olivia Lou, Edward Hyde, Noah Nathan, William A. Muller, Jochen Buck*, Lonny R. Levin, Carl Nathan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

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. JEM

Original languageEnglish (US)
Pages (from-to)353-361
Number of pages9
JournalJournal of Experimental Medicine
Volume202
Issue number3
DOIs
StatePublished - Aug 1 2005

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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