Counteracting effect of interferon-alpha and -beta on interferon- gamma-induced production of nitric oxide which is suppressive for antibody response.

We investigated the nitric oxide (NO)-mediated immunosuppressive activity of macrophages and the regulatory effect of type I (alpha and beta) interferons (IFNs) on IFN-gamma-induced NO production by macrophages. In the sheep red blood cell (SRBC)-specific secondary antibody response in vitro, the addition of macrophages to the culture of primed spleen cells substantially decreased the number of plaque-forming cells. The concentration of nitrite in the culture supernatant showed a positive correlation with the number of macrophages added in a dose- dependent manner, and the addition of NMMA, a potent inhibitor of NO production, resulted in the restoration of of the response. In addition, anti-IFN-gamma antibody abolished the ability of the immune culture supernatant to stimulate macrophages to produce NO. Therefore, the macrophage-dependent immunosuppression was due primarily to NO that was produced by macrophages in response to IFN-gamma derived from responding lymphocytes. The pretreatment of macrophages with IFN-alpha or -beta gave rise to a dramatic reduction of IFN-gamma-mediated NO production. In addition, the suppressive activity of these macrophages was much lower than that of untreated macrophages. These results indicate that type I IFNs can regulate the immune response by modulating IFN-gamma-induced production of immunosuppressive NO.