EARLY INTERLEUKIN-12 PRODUCTION BY MACROPHAGES IN RESPONSE TO MYCOBACTERIAL INFECTION DEPENDS ON INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA

Interleukin 12 (IL-12) produced by macrophages immediately after infec tion is considered essential for activation of a protective immune res ponse against intracellular pathogens. In the murine Mycobacterium bov is Bacillus Calmette-Guerin (BCG) model we assessed whether early IL-1 2 production by macrophages depends on other cytokines. In vitro, muri ne bone marrow-derived macrophages produced IL-12 after infection with viable M. bovis BCG or stimulation with LPS, however, priming with re combinant interferon gamma (rIFN-gamma) was necessary. In addition, IL -12 production by these macrophages was blocked by specific anti-tumor necrosis factor alpha (TNF-alpha) antiserum. Macrophages from gene de letion mutant mice lacking either the IFN-gamma receptor or the TNF re ceptor 1 (p55) failed to produce IL-12 in vitro after stimulation with rIFN-gamma and mycobacterial infection. In vivo, IL-12 production was induced in spleens of immunocompetent mice early during M. bovis BCG infection but not in those of mutant mice lacking the receptors for IF N-gamma or TNF. Our results show that IL-12 production by macrophages in response to mycobacterial infection depends on IFN-gamma and TNF. H ence, IL-12 is not the first cytokine produced in mycobacterial infect ions.