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Myelin basic protein-primed T cells induce nitric oxide synthase in microglial cells. Implications for multiple
Subhajit Dasgupta1, Malabendu Jana, Xiaojuan Liu
1Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska 68583, USA.
The Journal of Biological Chemistry
|August 15, 2002
Summary
Autoreactive T cells recognizing myelin basic protein (MBP) drive nitric oxide synthase (iNOS) in microglia via cell contact. Interferon-beta (IFN-beta) surprisingly enhances this, but also inhibits T cell interaction, offering a potential therapeutic avenue for multiple sclerosis (MS).
Area of Science:
- Neuroimmunology
- Autoimmune Diseases
- Cellular Immunology
Background:
- Autoreactive T cells targeting myelin antigens are critical for central nervous system autoimmune diseases like multiple sclerosis (MS).
- Microglia, the resident immune cells of the CNS, play a key role in neuroinflammation.
- Inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), a molecule implicated in inflammatory processes within the CNS.
Purpose of the Study:
- To investigate the role of myelin basic protein (MBP)-primed T cells in inducing iNOS expression in microglial cells.
- To elucidate the mechanism of contact-dependent induction of microglial iNOS by T cells.
- To examine the effect of interferon-beta (IFN-beta), a treatment for MS, on this T cell-microglia interaction.
Main Methods:
- Co-culture of MBP-primed T cells with mouse BV-2 microglial cells and primary microglia.
- Measurement of nitric oxide (NO) production and iNOS expression (protein and mRNA).
- Use of blocking antibodies against very late antigen-4 (VLA-4) on T cells and treatment with IFN-beta.
Main Results:
- MBP-primed T cells significantly induced NO production and iNOS expression in microglia, dependent on cell-cell contact.
- VLA-4 integrin on MBP-primed T cells was crucial for this contact-mediated induction of iNOS.
- IFN-beta alone induced NO production in microglia but inhibited T cell-induced NO production by reducing VLA-4 expression on T cells.
Conclusions:
- Neuroantigen-primed T cells can induce contact-mediated iNOS expression in microglia, potentially contributing to MS pathogenesis.
- VLA-4 plays a significant role in the interaction between T cells and microglia leading to iNOS induction.
- IFN-beta exhibits a dual effect: directly activating microglia but inhibiting T cell-mediated iNOS induction, suggesting complex therapeutic implications in MS.