Counteracting effect of interferon-α and -β on interferon-γ-induced production of nitric oxide which is suppressive for antibody response

Abstract

We investigated the nitric oxide (NO)-mediated immunosuppressive activity of macrophages and the regulatory effect of type I (α and β) interferons (IFNs) on IFN-γ-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 the response. In addition, anti-IFN-γ 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-γ derived from responding lymphocytes. The pretreatment of macrophages with IFN-α or -β gave rise to a dramatic reduction of IFN-γ-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-γ-induced production of immunosuppressive NO.