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 live 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 exogenous 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.
Sibley
L D
LD
Immunology Research Department, Gillis W. Long Hansen's Disease Center, United States Public Health Service Hospital, Carville, Louisiana 70721.
Krahenbuhl
J L
JL
D000818:Animals; D002478:Cells, Cultured; D015232:Dinoprostone; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007111:Immunity, Cellular; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D007918:Leprosy / Q000503:physiopathology*; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D051379:Mice; D009166:Mycobacterium leprae; D011458:Prostaglandins E / Q000096:biosynthesis; D013481:Superoxides / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D011458:Prostaglandins E; D013481:Superoxides; D007371:Interferon-gamma; D015232:Dinoprostone; D007213:Indomethacin