Cytokine interactions in experimental cutaneous leishmaniasis. II. Endogenous tumor necrosis factor‐α production by macrophages is induced by the synergistic action of interferon (IFN)‐γ and interleukin (IL) 4 and accounts for the antiparasitic effect mediated by IFN‐γ and IL 4

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Abstract
Tumor necrosis factor‐alpha (TNF‐α) strongly activates murine peritoneal macrophages (MΦ) for killing of amastigotes from Leishmania major in the presence of low amounts of interferon‐γ (IFN‐γ). Recently, we found that IFN‐γ and interleukin 4 (IL 4) also synergistically enhance the antileishmanial potential of MΦ. In this report, evidence is provided that the synergism of IFN‐γ and IL 4 is based on the ability of the lymphokines to induce the endogenous production of TNF‐α. First, both IFN‐γ and IL 4 as single agents and in combination were potent inducers of TNF‐α production by MΦ infected with L. major amastigotes. Second, the synergistic effect of IFN‐γ and IL 4 on parasite killing by MΦ strongly correlated with their synergistic effect on the release of TNF‐α. Third, the IFN‐γ/IL 4‐mediated parasite elimination was completely abrogated not only in the presence of antibodies to IFN‐γ and IL 4, but also with an antibody specific for TNF‐α. Consistent with the conclusion that endogenously produced TNF‐α accounts for the synergism of IL 4 with IFN‐γ is the finding that Nω‐monomethyl‐L‐arginine, an inhibitor of the L‐arginine‐dependent generation of microbicidal nitrogen intermediates, totally blocked the MΦ activation induced by IFN‐γ combined with IL 4 as well as by IFN‐γ combined with TNF‐α. These results underline the complex interplay of cytokines derived from lymphocytes and MΦ and the role of TNF‐α as pivotal factor for the induction of antileishmanial effector functions.