Induction of unresponsiveness to gamma interferon in macrophages infected with Mycobacterium leprae

We have previously demonstrated that Mycobacterium leprae-burdened granuloma macrophages isolated from infected nude mice are refractory to activation by gamma interferon (IFN-γ). To explore further both the afferent and efferent functional capacity of M. leprae-infected macrophages, we examined the IFN-γ-mediated activation of resident mouse peritoneal macrophages infected in vitro with live or dead M. leprae. When IFN-γ was administered within 24 h of M. leprae infection, macrophages were fully activated. However, defective activation was evident at 3 to 5 days postinfection in macrophages that were heavily burdened with viable M. leprae. This defect was evident by four parameters of activation in which IFN-γ failed to stimulate the enhancement of microbicidal activity, cytotoxicity for tumor target cells, O₂^- production, and surface Ia antigen expression. The development of defective activation closely followed an increase in macrophage production of prostaglandin E₂. Defective activation of M. leprae-burdened macrophages was reversible by indomethacin, and a similar block in IFN-γ activation was observed in three of these four parameters in normal macrophages treated with exogenous prostaglandin E₂. Thus, infection of mouse macrophages with M. leprae appears to restrict IFN-γ-mediated activation at least in part by induction of inhibitory levels of prostaglandin E₂.