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 upregulated 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 similar to 20-fold. STAT-1 alpha and NF-kappa B 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 Fast-expressing cells, similar to 20% of cells underwent Fas-mediated cell death, which increased to similar to 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-1 beta (MIP-1 beta), MIP-1 alpha, 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.
Publisher
AMER ASSOC IMMUNOLOGISTS
Issue Date
2000-02
Language
ENG
Keywords

CENTRAL-NERVOUS-SYSTEM; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; TRANSFORMING GROWTH FACTOR-BETA-1; SIGNALING COMPLEX DISC; T-CELLS; INDUCED APOPTOSIS; FACTOR-BETA; MULTIPLE-SCLEROSIS; PROTEIN-KINASE

Citation

JOURNAL OF IMMUNOLOGY, v.164, no.3, pp.1277 - 1285

ISSN
0022-1767
URI
http://hdl.handle.net/10203/74774
Appears in Collection
BiS-Journal Papers(저널논문)
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