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Cyclic AMP

Master Regulator of Innate Immune Cell Function

Divisions of ¹ Pulmonary and Critical Care Medicine and ² Infectious Diseases, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan

Correspondence and requests for reprints should be addressed to Marc Peters-Golden, M.D., 6301 MSRB III, 1150 W. Medical Center Drive, University of Michigan Health System, Ann Arbor, MI 48109-5642. E-mail: petersm{at}umich.edu

Cyclic adenosine monophosphate (cAMP) was the original "second messenger" to be discovered. Its formation is promoted by adenylyl cyclase activation after ligation of G protein–coupled receptors by ligands including hormones, autocoids, prostaglandins, and pharmacologic agents. Increases in intracellular cAMP generally suppress innate immune functions, including inflammatory mediator generation and the phagocytosis and killing of microbes. The importance of the host cAMP axis in regulating antimicrobial defense is underscored by the fact that microbes have evolved virulence-enhancing strategies that exploit it. Many clinical situations that predispose to infection are associated with increases in cAMP, and therapeutic strategies to interrupt cAMP generation or actions have immunostimulatory potential. This article reviews the anatomy of the cAMP axis, the mechanisms by which it controls phagocyte immune function, microbial strategies to dysregulate it, and its clinical relevance.

Key Words: phagocytes • host defense • G protein–coupled receptors • protein kinase A • exchange protein activated by cyclic AMP

CLINICAL RELEVANCE This review will provide clinicians with an overview of the cyclic AMP axis, its role as a down-regulator of host antimicrobial defense functions, and the clinical and translational relevance of such actions.