Showing papers by "Steffen Stenger published in 1991"

Cytokine interactions in experimental cutaneous leishmaniasis. Interleukin 4 synergizes with interferon‐γ to activate murine macrophages for killing of Leishmania major amastigotes

Abstract: We investigated the effect of recombinant murine interleukin 4 (IL 4) in the absence or presence of recombinant murine interferon-gamma (IFN-gamma) on adherent bone-marrow macrophages (M phi), peritoneal exudate and resident peritoneal M phi from susceptible BALB/c M phi, which were pulse-infected with Leishmania major amastigotes (AM), IL 4 (5-100 U/ml) failed to activate any of these M phi populations for killing of intracellular AM. However, in the presence of low concentrations of IFN-gamma (10-20 U/ml), which alone caused only a slight or intermediate reduction of the number of intracellular parasites. IL 4 led to a dramatic increase of the parasite elimination by all M phi populations. In the case of resident peritoneal M phi, the synergism of IFN-gamma and IL 4 required the incubation of the M phi with both cytokines or with IFN-gamma alone for at least 10 h prior to infection; adding both cytokines after infection of the M phi did not cause a significant reduction of the intracellular parasite burden. The synergistic effect of IL 4 and IFN-gamma was completely abrogated in the presence of anti-IL 4 antibodies. Furthermore, there was no significant difference between M phi derived from either susceptible BALB/c or from resistant C57BL/6 mice. Evidence is presented that the synergistic action of IL 4 and IFN-gamma occurs via an L-arginine-dependent killing pathway. From these data we conclude that IL 4 provides a strong stimulus for the killing of intracellular L. major AM provided low concentrations of IFN-gamma are present. Also, IFN-gamma is apparently an important priming signal for the activation of resident M phi to eliminate intracellular AM.

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

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

Cytokine interactions in experimental cutaneous leishmaniasis.

Abstract: Destruction of intracellularly living Leishmania major amastigotes is achieved by activated macrophages. In this report, we have investigated the contribution of IL-4, TNF-alpha and IFN-gamma to the induction of antileishmanial macrophage activation. It was found that as single lymphokine only IFN-gamma led to amastigote elimination by peritoneal exudate macrophages. Neither IL-4 nor TNF-alpha or the combination of both cytokines led to antimicrobial activation. When the macrophages were incubated with concentrations of IFN-gamma that by themselves were insufficient for maximum cell activation, it was found that both IL-4 and TNF-alpha very effectively synergized with IFN-gamma for induction of antiparasitic activity. The activation which was achieved when IFN-gamma was combined with IL-4 could be blocked not only with antibodies to either of the lymphokines, but also with an antiserum specific for TNF-alpha, suggesting the involvement of endogenously generated TNF-alpha in this synergism. Any of the synergistic activities observed presumably lead to the activation of the L-arginine dependent pathway used by the cell for the production of nitrogen oxides as effector molecules for parasite killing since NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of this pathway, completely blocked the killing of intracellular parasites. We conclude that macrophage activation for antiparasitic activity is directed by a complex network of cytokine-interactions, in which IL-4 and TNF-alpha very effectively synergize positively with low levels of IFN-gamma.