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-.gamma.). To explore further both the afferent and efferent functional capacity of M. leprae-infected macrophages, we examined the IFN-.gamma.-mediated activation of resident mouse peritoneal macrophages infected in vitro with liver or dead M. leprae. When IFN-.gamma. 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-.gamma. 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-.gamma. activation was observed in three of these four parameters in normal macrophages treated with exogeneous prostaglandin E2. Thus, infection of mouse macrophages with M. leprae appears to restrict IFN-.gamma.-mediated activation at least in part by induction of inhibitory levels of prostaglandin E2.