title: A new function of the Fas-FasL pathway in macrophage activation.
abstract: Upon infection with the protozoan parasite Leishmania major, susceptible BALB/c mice develop unhealing lesions associated with the maturation of CD4(+)Th2 cells secreting IL-4. In contrast, resistant C57BL/6 mice heal their lesions, because of expansion and secretion of IFN-gamma of CD4(+) Th1 cells. The Fas-FasL pathway, although not involved in Th cell differentiation, was reported to be necessary for complete resolution of lesions. We investigate here the role of IFN-gamma and IL-4 on Fas-FasL nonapoptotic signaling events leading to the modulation of macrophage activation. We show that addition of FasL and IFN-gamma to BMMø led to their increased activation, as reflected by enhanced secretion of TNF, IL-6, NO, and the induction of their microbicidal activity, resulting in the killing of intracellular L. major. In contrast, the presence of IL-4 decreased the synergy of IFN-gamma/FasL significantly on macrophage activation and the killing of intracellular L. major. These results show that FasL synergizes with IFN-gamma to activate macrophages and that the tight regulation by IFN-gamma and/or IL-4 of the nonapoptotic signaling events triggered by the Fas-FasL pathway affects significantly the activation of macrophages to a microbicidal state and may thus contribute to the pathogenesis of L. major infection.
authors.affiliation: World Health Organization Immunology Research and Training Centre, University of Lausanne, Epalinges, Switzerland.
authors.forename: Reza
authors.initials: R
authors.lastname: Chakour
authors.forename: Cindy
authors.initials: C
authors.lastname: Allenbach
authors.forename: Florian
authors.initials: F
authors.lastname: Desgranges
authors.forename: Mélanie
authors.initials: M
authors.lastname: Charmoy
authors.forename: Jacques
authors.initials: J
authors.lastname: Mauel
authors.forename: Irène
authors.initials: I
authors.lastname: Garcia
authors.forename: Pascal
authors.initials: P
authors.lastname: Launois
authors.forename: Jacques
authors.initials: J
authors.lastname: Louis
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tacchini-Cottier
mesh_terms: D000818:Animals; D053222:Fas Ligand Protein / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D018320:Leishmania major / Q000276:immunology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D015398:Signal Transduction / Q000276:immunology*; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D019014:fas Receptor; D015847:Interleukin-4; D007371:Interferon-gamma