The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published online 25 July 2005 doi:10.1084/jem.20050778
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 3, 353-361
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BRIEF DEFINITIVE REPORT

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

Hyunsil Han1,4, Alexander Stessin2,5, Julia Roberts1, Kenneth Hess2, Narinder Gautam3,4, Margarita Kamenetsky2, Olivia Lou3,4, Edward Hyde7, Noah Nathan1, William A. Muller3,4, Jochen Buck2,5, Lonny R. Levin2,5, and Carl Nathan1,4,6

1 Department of Microbiology and Immunology, Weill Medical College of Cornell University
2 Department of Pharmacology, Weill Medical College of Cornell University
3 Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University
4 Graduate Programs in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University
5 Pharmacology, Weill Medical College of Cornell University
6 Molecular Biology, Weill Medical College of Cornell University
7 High Throughput Screening Resource Center, The Rockefeller University, New York, NY 10021

CORRESPONDENCE Carl Nathan: cnathan{at}med.cornell.edu OR Jochen Buck: jobuck{at}med.cornell.edu

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.


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