Monocyte chemotactic protein-1 stimulates the killing of leishmania major by human monocytes, acts synergistically with IFN-gamma and is antagonized by IL-4.
We recently demonstrated that monocyte chemotactic protein-1 (MCP-1) is strongly expressed in lesions of patients with self-healing localized cutaneous leishmaniasis (LCL) whereas it is scarce in those of chronic diffuse cutaneous 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 directly stimulates the elimination of intracellular Leishmania parasites by human monocytes, a potential that correlates with the induction of reactive oxygen intermediates. Release of NO was not detected. To understand the cross-talk between the chemokine and T cell-associated cytokines, we studied the influence of the Th1 cytokine IFN-gamma and the Th2 cytokine IL-4 on MCP-1-mediated activation of human monocytes. The data demonstrate that IFN-gamma and MCP-1 synergistically activate monocytes to clear intracellular parasites, whereas IL-4 abrogates the effect of MCP-1. Furthermore, IL-4 inhibits 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 macrophage activation in cutaneous leishmaniasis. In lesions of LCL, the synergistic 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 lesions may favor the suppression of MCP-1 and, together with the lack of IFN-gamma, the progression of disease.
Ritter
U
U
Institute for Molecular Biology of Infectious Diseases, University of Würzburg, Würzburg, Germany.
Moll
H
H
D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000276:immunology*; D004336:Drug Antagonism; D004357:Drug Synergism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D015847:Interleukin-4 / Q000276:immunology*; D018320:Leishmania major / Q000276:immunology*; D009000:Monocytes / Q000276:immunology* / Q000469:parasitology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
D018932:Chemokine CCL2; D015847:Interleukin-4; D007371:Interferon-gamma