Interferon-gamma induces apoptosis and augments the expression of Fas and Fas ligand by microglia in vitro

Exp Neurol. 2000 Apr;162(2):290-6. doi: 10.1006/exnr.1999.7345.


Activation of microglia by interferon-gamma (IFN-gamma) has been implicated in a number of central nervous system (CNS) inflammatory disease processes. Because IFN-gamma has also been shown to play a role in programmed cell death, we investigated its cytotoxicity and its effect on the Fas apoptotic pathway in microglia. Flow cytometry was used to quantify the IFN-gamma-mediated apoptotic response and Fas and Fas ligand (FasL) expression in two well-characterized murine microglia cell lines (BV-2 and N9). Nuclear fragmentation, suggestive of apoptosis, was noted within 24 h of incubation of microglia with IFN-gamma (10 U/ml). After a 72-h incubation, almost every BV-2 and N9 microglia, but not GL261 glioma cells, underwent cell death and detached from the culture plates. This cytotoxicity occurred even at low IFN-gamma concentrations (1 U/ml) and was inhibited by BAF, a pan-caspase inhibitor. Incubation of BV-2 and N9 microglia, but not GL261 glioma cells, with IFN-gamma also potentiated the expression of Fas and FasL in a similar dose-response and time-course manner, as seen for the apoptotic response. Whereas Fas expression increased by 100% in both microglia cells, FasL upregulation was more pronounced and increased by as much as 200% in the N9 cells. These findings suggest that in addition to its role as a microglia activator, IFN-gamma may also induce apoptosis of microglia, possibly through simultaneous upregulation of Fas and FasL. Interferon-gamma modulation of the Fas pathway and apoptosis in microglia may be important in the pathogenesis of inflammatory CNS disease processes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Animals
  • Antigens, Surface / biosynthesis
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspase Inhibitors
  • Cell Line
  • Dose-Response Relationship, Drug
  • Fas Ligand Protein
  • Flow Cytometry
  • Glioma / metabolism*
  • Glioma / pathology
  • Interferon-gamma / pharmacology*
  • Ligands
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Proteins / biosynthesis
  • Mice
  • Microglia / cytology
  • Microglia / metabolism*
  • Up-Regulation
  • fas Receptor / biosynthesis*


  • Amino Acid Chloromethyl Ketones
  • Antigens, Surface
  • Caspase Inhibitors
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Ligands
  • Membrane Glycoproteins
  • Membrane Proteins
  • butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone
  • fas Receptor
  • Interferon-gamma