Selective modulation of lipopolysaccharide-stimulated cytokine expression and mitogen-activated protein kinase pathways by dibutyryl-cAMP in BV2 microglial cells

Brain Res Mol Brain Res. 2003 May 12;113(1-2):86-96. doi: 10.1016/s0169-328x(03)00095-0.


Cyclic AMP is a very important regulator in a wide range of biological processes, including inflammatory reactions. To investigate the role of cAMP in microglia, we examined the effect of dibutyryl-cAMP (dbcAMP) on lipopolysaccharide (LPS)-stimulated cytokine expression and signaling pathways in murine BV2 microglial cells. DbcAMP strongly suppressed LPS-induced TNF-alpha expression, without affecting NO, IL-6 or TGF-beta1 expression. In contrast, LPS-induced IL-1beta or IL-10 expressions were dramatically increased by dbcAMP. We further examined the effect of elevated cAMP on signaling molecules such as MAP kinases (p38 MAPK, ERK and JNK), NF-kappaB and AP1, which are involved in the regulation of inflammatory responses. DbcAMP decreased the LPS-induced phosphorylation of p38 MAPK, while it modestly enhanced the ERK activity. JNK phosphorylation was slightly reduced by dbcAMP only at the later time point. Electrophoretic mobility shift assay revealed that the elevated cAMP potentiated AP-1 binding activity by enhancing c-fos binding. On the other hand, dbcAMP repressed NF-kappaB-mediated transcription without affecting NF-kappaB binding. Treatment with H89, a selective inhibitor of protein kinase A, completely reversed cAMP-induced IL-10 and IL-1beta upregulation but only partially reversed the cAMP-induced repression of TNF-alpha. Thus, the effect of dbcAMP in BV2 cells appears to be mediated through both protein kinase A-dependent and -independent pathways. Taken together, our results demonstrate that cAMP modulates microglia activation in a diverse and complex manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / enzymology*
  • Bucladesine / pharmacology
  • Cell Line, Transformed
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / drug effects
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Cytokines / drug effects
  • Cytokines / metabolism*
  • Encephalitis / chemically induced
  • Encephalitis / enzymology*
  • Encephalitis / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Gliosis / chemically induced
  • Gliosis / enzymology*
  • Gliosis / physiopathology
  • Interleukins / metabolism
  • Lipopolysaccharides / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Microglia / drug effects
  • Microglia / enzymology*
  • NF-kappa B / drug effects
  • NF-kappa B / metabolism
  • Phosphorylation / drug effects
  • Transcription Factor AP-1 / drug effects
  • Transcription Factor AP-1 / metabolism
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism


  • Cytokines
  • Enzyme Inhibitors
  • Interleukins
  • Lipopolysaccharides
  • NF-kappa B
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • Bucladesine
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases