TUMOR NECROSIS FACTOR-ALPHA IN COMBINATION WITH INTERFERON-GAMMA, BUT NOT WITH INTERLEUKIN-4 ACTIVATES MURINE MACROPHAGES FOR ELIMINATION OF LEISHMANIA-MAJOR AMASTIGOTES

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. Copyright © 1990 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim