A new function of the Fas-FasL pathway in macrophage activation

J Leukoc Biol. 2009 Jul;86(1):81-90. doi: 10.1189/jlb.1008590. Epub 2009 Apr 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fas Ligand Protein / pharmacology*
  • Interferon-gamma / pharmacology
  • Interleukin-4 / pharmacology
  • Leishmania major / immunology
  • Macrophage Activation*
  • Macrophages / metabolism
  • Macrophages / parasitology
  • Mice
  • Mice, Inbred BALB C
  • Signal Transduction / immunology*
  • fas Receptor / metabolism*


  • Fas Ligand Protein
  • fas Receptor
  • Interleukin-4
  • Interferon-gamma