Differential regulation and function of Fas expression on glial cells.
Fas/Apo-1 is a member of the TNF receptor superfamily that signals apoptotic cell death in susceptible target cells. Fas or Fas ligand (FasL)-deficient mice are relatively resistant to the induction of experimental allergic encephalomyelitis, implying the involvement of Fas/FasL in this disease process. We have examined the regulation and function of Fas expression in glial cells (astrocytes and microglia). Fas is constitutively expressed by primary murine microglia at a low level and significantly up-regulated by TNF-alpha or IFN-gamma stimulation. Primary astrocytes express high constitutive levels of Fas, which are not further affected by cytokine treatment. In microglia, Fas expression is regulated at the level of mRNA expression; TNF-alpha and IFN-gamma induced Fas mRNA by approximately 20-fold. STAT-1alpha and NF-kappaB activation are involved in IFN-gamma- or TNF-alpha-mediated Fas up-regulation in microglia, respectively. The cytokine TGF-beta inhibits basal expression of Fas as well as cytokine-mediated Fas expression by microglia. Upon incubation of microglial cells with FasL-expressing cells, approximately 20% of cells underwent Fas-mediated cell death, which increased to approximately 60% when cells were pretreated with either TNF-alpha or IFN-gamma. TGF-beta treatment inhibited Fas-mediated cell death of TNF-alpha- or IFN-gamma-stimulated microglial cells. In contrast, astrocytes are resistant to Fas-mediated cell death, however, ligation of Fas induces expression of the chemokines macrophage inflammatory protein-1beta (MIP-1beta), MIP-1alpha, and MIP-2. These data demonstrate that Fas transmits different signals in the two glial cell populations: a cytotoxic signal in microglia and an inflammatory signal in the astrocyte.
Lee
S J
SJ
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Zhou
T
T
Choi
C
C
Wang
Z
Z
Benveniste
E N
EN
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D002461:Cell Line, Transformed; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins / Q000502:physiology; D007106:Immune Sera / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000378:metabolism*; D016328:NF-kappa B / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000502:physiology; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*
D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D007106:Immune Sera; D008024:Ligands; D016328:NF-kappa B; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D019014:fas Receptor