INDUCTION OF MACROPHAGE NITRIC-OXIDE PRODUCTION BY INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA IS ENHANCED BY INTERLEUKIN-10

Interleukin-10 (IL-10) has been reported to inhibit nitric oxide (NO) synthesis and microbicidal activity of interferon-gamma (IFN-gamma)-st imulated macrophages (MPHI) by preventing the secretion of tumor necro sis factor-alpha (TNF-alpha) which serves as an autocrine activating s ignal.We have examined the effects of recombinant IL-10 on the capacit y of IFN-gamma together with exogenous TNF-alpha to induce NO synthesi s by bone marrow-derived MPHI. Under these conditions and in contrast to its reported deactivating potential, IL-10 strongly enhanced NO syn thesis measured as nitrite (NO2-) release (half maximal stimulation at approximately 10 U/ml). IL-10 further increased NO2- production by MP HI stimulated in the presence of optimal concentrations of prostagland in E2, a positive modulator of MPHI activation by IFN-gamma/TNF-alpha. Increased steady state levels of NO synthase mRNA were observed in 4- h IFN-gamma/TNF-alpha cultures and enhanced NO2-release was evident 24 h but not 48 h after stimulation. These results suggest that the effe cts of IL-10 on MPHI function are more complex than previously recogni zed.