Cutting edge: macrophage inhibition by cyclic AMP (cAMP): differential roles of protein kinase A and exchange protein directly activated by cAMP-1.

Aronoff DM, Canetti C, Serezani CH, Luo M, Peters-Golden M
J Immunol. 2005 174 (2): 595-9

PMID: 15634874 · DOI:10.4049/jimmunol.174.2.595

cAMP has largely inhibitory effects on components of macrophage activation, yet downstream mechanisms involved in these effects remain incompletely defined. Elevation of cAMP in alveolar macrophages (AMs) suppresses FcgammaR-mediated phagocytosis. We now report that protein kinase A (PKA) inhibitors (H-89, KT-5720, and myristoylated PKA inhibitory peptide 14-22) failed to prevent this suppression in rat AMs. We identified the expression of the alternative cAMP target, exchange protein directly activated by cAMP-1 (Epac-1), in human and rat AMs. Using cAMP analogs that are highly specific for PKA (N6-benzoyladenosine-3',5'-cAMP) or Epac-1 (8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cAMP), we found that activation of Epac-1, but not PKA, dose-dependently suppressed phagocytosis. By contrast, activation of PKA, but not Epac-1, suppressed AM production of leukotriene B(4) and TNF-alpha, whereas stimulation of either PKA or Epac-1 inhibited AM bactericidal activity and H(2)O(2) production. These experiments now identify Epac-1 in primary macrophages, and define differential roles of Epac-1 vs PKA in the inhibitory effects of cAMP.

MeSH Terms (17)

Animals Anti-Bacterial Agents Cell Line Cells, Cultured Cyclic AMP Cyclic AMP-Dependent Protein Kinases Down-Regulation Enzyme Activation Guanine Nucleotide Exchange Factors Inflammation Mediators Macrophage Activation Macrophages, Alveolar Mice Phagocytosis Rats Rats, Wistar Receptors, Fc

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