Cyclic AMP: master regulator of innate immune cell function

Abstract

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.

Figure 1.

The regulation of cyclic AMP (cAMP) levels and antimicrobial actions. The binding of an agonist to the G protein–coupled receptor (GPCR) induces a conformational change resulting in the liberation of the Gα subunit from the βγ subunit complex. The binding of the Gα subunit to adenylyl cyclase (AC) either stimulates (Gαs) or inhibits (Gαi) the enzyme's generation of cAMP. The production of cAMP is also regulated by microbial pathogens. Pertussis toxin and cholera toxin cause elevated cAMP levels through ADP-ribosylation of either the Gαi subunit to prevent its inhibition of AC or of the Gαs subunit to constitutively activate AC, respectively. Phosphodiesterases (PDEs), which degrade cAMP to AMP, are another regulator of intracellular cAMP levels. PDE inhibitors prevent such degradation, resulting in accumulation of intracellular cAMP. The downstream signaling of cAMP is mediated by its interactions with effector molecules, protein kinase A (PKA) or exchange proteins directly activated by cAMP (Epac), which have been shown to modulate phagocyte functions. Depicted here is a pattern demonstrated for alveolar macrophages in which specific antimicrobial functions are differentially regulated by particular cAMP effectors.