Opposite effects of interferon-gamma and prostaglandin E2 on tumor necrosis factor and interleukin-10 production in microglia: a regulatory loop controlling microglia pro- and anti-inflammatory activities

J Neurosci Res. 1999 Jun 15;56(6):571-80. doi: 10.1002/(SICI)1097-4547(19990615)56:6<571::AID-JNR3>3.0.CO;2-P.


Following brain injury, microglial cells produce pro- and anti-inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-10 (IL-10). IL-10 provides an efficient autocrine mechanism for controlling microglia activation. To elucidate the mechanisms that regulate the cytokine profile of microglia, we examined the effects of several immunomodulators on IL-10 and TNF production by cultured mouse microglia. Lipopolysaccharide (LPS) was the only inducer of IL-10 and TNF gene expression and secretion. The T helper 1-type cytokine interferon-gamma (IFN-gamma) induced TNF transcripts, but not TNF secretion, and suppressed LPS-induced IL-10 mRNA and secretion by microglia. Opposite to IFN-gamma, the lipid mediator prostaglandin E2 (PGE2) enhanced the LPS-induced production of IL-10 and inhibited that of TNF. The effects of PGE2 on cytokine gene expression and secretion were antagonized by IFN-gamma. Agents that increase cAMP levels mimicked the action of PGE2 on cytokine secretion, indicating the involvement of cAMP-coupled prostaglandin receptors. In conclusion, IFN-gamma and PGE2, two mediators released at inflammatory sites, differentially regulate the production of a proinflammatory and an anti-inflammatory cytokine in microglia. We suggest that the activity and role of microglia in the damaged CNS could be finely tuned by the local concentration ratio of these mediators.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cytokines / pharmacology
  • Dinoprostone / pharmacology*
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology*
  • Inflammation / prevention & control
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / pharmacology*
  • Interleukin-10 / genetics*
  • Isoproterenol / pharmacology
  • Kinetics
  • Lipopolysaccharides / pharmacology
  • Mice
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / immunology*
  • Prosencephalon / cytology
  • Prosencephalon / immunology
  • RNA, Messenger / genetics
  • Recombinant Proteins
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription, Genetic / drug effects
  • Transcription, Genetic / immunology
  • Tumor Necrosis Factor-alpha / genetics*


  • Cytokines
  • Lipopolysaccharides
  • RNA, Messenger
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma
  • Dinoprostone
  • Isoproterenol