IFN-gamma inhibits the suppressive effects of PGE2 on the production of tumor necrosis factor-alpha by mouse macrophages.
Tumor necrosis factor-alpha (TNF-alpha) has become known as a central mediator of responses to endotoxin, rheumatoid diseases, and other forms of inflammation. Current investigations indicate that the production of TNF-alpha is controlled by other mediators, including interferon-gamma (IFN-gamma) and prostaglandin E2 (PGE2). In the present study, we investigated the regulatory effects of IFN-gamma and/or PGE2 on LPS-induced TNF-alpha production and mRNA expression in mouse peritoneal macrophages using the enzyme immunoassay and Northern blot analysis, respectively. In response to 10 ng/ml of LPS, TNF-alpha production reached a maximum at approximately 4 hrs, followed by rapid decline. At the molecular level, TNF-alpha mRNA accumulated rapidly after LPS exposure, reaching a peak by 3 hr, and declined more rapidly than did the production of TNF-alpha. Exposure of macrophages to 100 U/ml of IFN-gamma caused an increase in both the TNF-alpha production and mRNA expression induced by LPS. Exogenous PGE2 caused a dose dependent reduction in LPS-induced TNF-alpha mRNA accumulation as well as TNF-alpha production. Macrophages primed with IFN-gamma showed the reduced responsiveness to the suppressive effect of PGE2 on the production of TNF-alpha and the accumulation of TNF-alpha mRNA. These findings indicate that the suppressive effects induced by PGE2 on the accumulation of TNF-alpha mRNA as well as the production of TNF-alpha can be reduced by the pretreatment of macrophages with IFN-gamma. These studies demonstrate the role of IFN-gamma as an immunomodulating compound that may effectively regulate TNF-alpha production by modulation of macrophage responsiveness to PGE2.
Department of Pediatrics, College of Medicine and Institute of Allergy and Clinical Immunology, Medical Research Center, Seoul National University, Korea. jgkim@plaza.snu.ac.kr
J G
JG
Kim
Y S
YS
Hahn
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018836:Inflammation Mediators; D007371:Interferon-gamma / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D015232:Dinoprostone