CYTOKINE INTERACTIONS IN EXPERIMENTAL CUTANEOUS LEISHMANIASIS - INTERLEUKIN-4 SYNERGIZES WITH INTERFERON-GAMMA TO ACTIVATE MURINE MACROPHAGES FOR KILLING OF LEISHMANIA-MAJOR AMASTIGOTES

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.