A new function of the Fas-FasL pathway in macrophage activation.
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.
Chakour
Reza
R
World Health Organization Immunology Research and Training Centre, University of Lausanne, Epalinges, Switzerland.
Allenbach
Cindy
C
Desgranges
Florian
F
Charmoy
Mélanie
M
Mauel
Jacques
J
Garcia
Irène
I
Launois
Pascal
P
Louis
Jacques
J
Tacchini-Cottier
Fabienne
F
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*
D053222:Fas Ligand Protein; D019014:fas Receptor; D015847:Interleukin-4; D007371:Interferon-gamma