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

J Immunol. 2005 Jan 15;174(2):595-9. doi: 10.4049/jimmunol.174.2.595.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / immunology
  • Anti-Bacterial Agents / metabolism
  • Cell Line
  • Cells, Cultured
  • Cyclic AMP / physiology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cyclic AMP-Dependent Protein Kinases / physiology*
  • Down-Regulation / immunology*
  • Enzyme Activation / immunology
  • Guanine Nucleotide Exchange Factors / biosynthesis
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanine Nucleotide Exchange Factors / physiology*
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Inflammation Mediators / physiology
  • Macrophage Activation / immunology
  • Macrophages, Alveolar / enzymology
  • Macrophages, Alveolar / immunology*
  • Macrophages, Alveolar / metabolism*
  • Macrophages, Alveolar / microbiology
  • Mice
  • Phagocytosis / immunology
  • Rats
  • Rats, Wistar
  • Receptors, Fc / antagonists & inhibitors
  • Receptors, Fc / physiology

Substances

  • Anti-Bacterial Agents
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Inflammation Mediators
  • Receptors, Fc
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases