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Differential regulation and function of Fas expression on glial cells
1Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Abstract:
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.
Insights
The Fas receptor plays distinct roles in glial cells. In microglia, it triggers cell death, while in astrocytes, it promotes inflammation, suggesting differential functions in neurological diseases.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
Background:
- The Fas/Apo-1 receptor, part of the TNF receptor superfamily, mediates apoptotic cell death.
- Fas/Fas ligand (FasL) involvement is implied in experimental allergic encephalomyelitis, a neuroinflammatory disease.
Purpose of the Study:
- To investigate the regulation and function of Fas expression in astrocytes and microglia.
- To understand the differential signaling pathways of Fas in these glial cells.
Main Methods:
- Primary murine microglia and astrocytes were cultured.
- Fas expression levels were analyzed via mRNA and protein.
- Cytokine (TNF-alpha, IFN-gamma, TGF-beta) and FasL treatments were applied.
- Activation of transcription factors (STAT-1alpha, NF-kappaB) was assessed.
- Chemokine expression (MIP-1beta, MIP-1alpha, MIP-2) was measured.
Main Results:
- Microglia constitutively express low Fas levels, significantly upregulated by TNF-alpha or IFN-gamma via mRNA.
- Astrocytes express high constitutive Fas levels, unaffected by cytokines.
- STAT-1alpha and NF-kappaB mediate IFN-gamma and TNF-alpha induced Fas upregulation in microglia, respectively.
- TGF-beta inhibits basal and cytokine-induced Fas expression and Fas-mediated cell death in microglia.
- Microglia undergo Fas-mediated cell death upon FasL stimulation, enhanced by TNF-alpha/IFN-gamma.
- Astrocytes are resistant to Fas-mediated cell death but upregulate chemokines upon Fas ligation.
Conclusions:
- Fas signaling in microglia leads to cytotoxic effects, modulated by inflammatory cytokines.
- Fas signaling in astrocytes induces an inflammatory response via chemokine production.
- These distinct Fas functions in glial cells have implications for neuroinflammatory conditions.