Cutting edge: macrophage inhibition by cyclic AMP (cAMP): differential roles of protein kinase A and exchange protein directly activated by cAMP-1.
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.
Aronoff
David M
DM
Division of Infectious Disease, Department of Internal Medicine, University of Michigan Health System, Ann Arbor 48109-0642, USA.
Canetti
Claudio
C
Serezani
Carlos H
CH
Luo
Ming
M
Peters-Golden
Marc
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D010587:Phagocytosis / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D011961:Receptors, Fc / Q000037:antagonists & inhibitors / Q000502:physiology
D000900:Anti-Bacterial Agents; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D018836:Inflammation Mediators; D011961:Receptors, Fc; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases