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Roles of TNF-related apoptosis-inducing ligand in experimental autoimmune encephalomyelitis
B Hilliard1, A Wilmen, C Seidel
1Department of Molecular and Cellular Engineering, Institute for Human Gene Therapy, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Abstract:
TRAIL, the TNF-related apoptosis-inducing ligand, induces apoptosis of tumor cells, but not normal cells; the roles of TRAIL in nontransformed tissues are unknown. Using a soluble TRAIL receptor, we examined the consequences of TRAIL blockade in an animal model of multiple sclerosis. We found that chronic TRAIL blockade in mice exacerbated experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein. The exacerbation was evidenced primarily by increases in disease score and degree of inflammation in the CNS. Interestingly, the degree of apoptosis of inflammatory cells in the CNS was not affected by TRAIL blockade, suggesting that TRAIL may not regulate apoptosis of inflammatory cells in experimental autoimmune encephalomyelitis. By contrast, myelin oligodendrocyte glycoprotein-specific Th1 and Th2 cell responses were significantly enhanced in animals treated with the soluble TRAIL receptor. Based on these observations, we conclude that unlike TNF, which promotes autoimmune inflammation, TRAIL inhibits autoimmune encephalomyelitis and prevents activation of autoreactive T cells.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) blockade worsened experimental autoimmune encephalomyelitis in mice. TRAIL appears to inhibit autoimmune inflammation and T cell activation, contrary to TNF.
Area of Science:
- Immunology
- Neuroscience
- Cell Biology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but its role in normal tissues is largely unknown.
- Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS).
Purpose of the Study:
- To investigate the role of TRAIL in autoimmune inflammation using a mouse model of multiple sclerosis.
- To determine the effects of blocking TRAIL signaling on experimental autoimmune encephalomyelitis (EAE).
Main Methods:
- Utilized a soluble TRAIL receptor to block TRAIL activity in a mouse model of EAE induced by myelin oligodendrocyte glycoprotein.
- Assessed disease severity, CNS inflammation, inflammatory cell apoptosis, and T cell responses.
Main Results:
- Chronic TRAIL blockade exacerbated EAE, indicated by increased disease scores and CNS inflammation.
- TRAIL blockade did not affect the apoptosis of inflammatory cells in the CNS.
- Myelin oligodendrocyte glycoprotein-specific Th1 and Th2 cell responses were significantly enhanced by TRAIL blockade.
Conclusions:
- TRAIL inhibits autoimmune encephalomyelitis, contrasting with TNF's pro-inflammatory role.
- TRAIL appears to prevent the activation of autoreactive T cells, suggesting a regulatory function in autoimmune responses.