IFN-gamma inhibits the suppressive effects of PGE(2) on the production of tumor necrosis factor-alpha by mouse macrophages

Tumor necrosis factor-alpha (TNF-alpha) has become known as a central media tor of responses to endotoxin, rheumatoid diseases, and other forms of infl ammation. Current investigations indicate that the production of TNF-alpha is controlled by other mediators, including interferon-gamma (IFN-gamma) an d prostaglandin E-2 (PGE(2)). Ln the present study, we investigated the reg ulatory effects of IFN-gamma and/or PGE(2) on LPS-induced TNF-alpha product ion and mRNA expression in mouse peritoneal macrophages using the enzyme im munoassay and Northern blot analysis, respectively. In response to 10 ng/ml of LPS, TNF-alpha production reached a maximum at approximately 4 hrs, fol lowed by rapid decline. At the molecular level, TNF-alpha mRNA accumulated rapidly after LPS exposure, reaching a peak by 3 hr, and declined more rapi dly 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 mRN A expression induced by LPS. Exogenous PGE(2) caused a dose dependent reduc tion in LPS-induced TNF-alpha mRNA accumulation as well as TNF-alpha produc tion. Macrophages primed with IFN-gamma showed the reduced responsiveness t o the suppressive effect of PGE(2) on the production of TNF-alpha and the a ccumulation of TNF-alpha mRNA. These findings indicate that the suppressive effects induced by PGE(2) on the accumulation of TNF-alpha mRNA as well as the production of TNF-alpha can be reduced by the pretreatment of macropha ges with IFN-gamma. These studies demonstrate the role of IFN-gamma as an i mmunomodulating compound that may effectively regulate TNF-alpha production by modulation of macrophage responsiveness to PGE(2).