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.
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.
Aloisi
F
F
Laboratory of Organ and System Pathophysiology, Istituto Superiore di Sanità, Roma, Italy. fos4@iss.it
De Simone
R
R
Columba-Cabezas
S
S
Levi
G
G
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D007249:Inflammation / Q000517:prevention & control; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics*; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016548:Prosencephalon / Q000166:cytology / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D015232:Dinoprostone; D007545:Isoproterenol