Tumor necrosis factor‐α in combination with interferon‐γ, but not with interleukin 4 activates murine macrophages for elimination of Leishmania major amastigotes

Abstract

We have previously shown that during an infection with Leishmania major, susceptible BALB/c mice, as opposed to mice of a resistant strain (C57BL/6), are primed by lipopolysaccharide for the production of high levels of tumor necrosis factor-α (TNF-α) which is known to be a potent macrophage (MΦ) stimulator in other parasitic diseases. In the present study we investigated whether TNF-α activates MΦ for killling of L. major parasites. In the absence of interferon-γ (IFN-γ) or lipopolysaccharide, TNF-α (0.025—25000 U/ml) failed to activate peritoneal exudate MΦ from BALB/c micefor killling of L. major amastigotes. In the presence of suboptimal doses of IFN-γ (5 or 10 U/ml), however, TNF-α mediated a rapid elimination of intracellular parasites, which was highly significant compared to IFN-γ alone. The combination of TNF with interleukin 4, in contrast, was inactive in this respect and allowed survival of intracellular parasites. From these data we conclude that thepresence of IFN-γ is curcial for TNF-α-mediated killing of L. major parasites by MΦ. Disease progression in susceptible mice thereforeseems to be a consequence of a deficiency of IFN-γ and a predominance of interleukin 4 rather than the result of an excess amount of TNF-α.