Monocyte chemotactic protein-1 stimulates the killing of Leishmania major by human monocytes, acts synergistically with IFN-gamma, and is antagonizedby IL-4

We recently demonstrated that monocyte chemotactic protein-1 (MCP-1) is str ongly expressed in lesions of patients with self-healing localized cutaneou s leishmaniasis (LCL) whereas it is scarce in those of chronic diffuse cuta neous leishmaniasis (DCL). This finding indicated that MCP-1 may contribute to the healing process. In the present study, we analyzed the capacity of MCP-1 to trigger leishmanicidal activities. The results show that MCP-1 dir ectly stimulates the elimination of intracellular Leishmania parasites by h uman monocytes, a potential that correlates with the induction of reactive oxygen intermediates. Release of NO was not detected. To understand the cro ss-talk between the chemokine and T cell-associated cytokines, we studied t he influence of the Th1 cytokine IFN-gamma and the Th2 cytokine IL-4 on MOP -1-mediated activation of human monocytes. The data demonstrate that lFN-ga mma and MOP-1 synergistically activate monocytes to clear intracellular par asites, whereas IL-4 abrogates the effect of MCP-1. Furthermore, IL-4 inhib its MCP-1 expression by infected monocytes, a finding that may explain the lack of MCP-1 in chronic lesions. The data suggest a novel model for macrop hage activation in cutaneous leishmaniasis. In lesions of LCL, the synergis tic action of MCP-1 and IFN-gamma may stimulate the killing of parasites by macrophages and promote healing, whereas the presence of IL-4 in DCL lesio ns may favor the suppression of MCP-1 and, together with the lack of IFN-ga mma, the progression of disease.