Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon γ and tumor necrosis factor α

Interleukin 12 (IL-12) produced by macrophages immediately after infection is considered essential for activation of a protective immune response against intracellular pathogens. In the murine Mycobacterium bovis Bacillus Calmette-Guerin (BCG) model we assessed whether early IL-12 production by macrophages depends on other cytokines. In vitro, murine bone marrow derived macrophages produced IL-12 after infection with viable M. bovis BCG or stimulation with LPS, however, priming with recombinant interferon γ (rIFN- γ) was necessary. In addition, IL-12 production by these macrophages was blocked by specific anti-tumor necrosis factor α (TNF-α) antiserum. Macrophages from gene deletion mutant mice lacking either the IFN-γ receptor or the TNF receptor 1 (p55) failed to produce IL-12 in vitro after stimulation with rIFN-γ 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 IFN-γ or TNF. Our results show that IL-12 production by macrophages in response to mycobacterial infection depends on IFN-γ and TNF. Hence, IL-12 is not the first cytokine produced in mycobacterial infections.