Abstract
The presence of autoreactive T cells recognizing self myelin antigens is necessary for the development of central nervous system autoimmune diseases such as multiple sclerosis (MS). The present study was undertaken to investigate the role of myelin basic protein (MBP)-primed T cells in the expression of inducible nitric oxide synthase (iNOS) in microglial cells. MBP-primed T cells alone markedly induced the production of NO and the expression of iNOS protein and mRNA in mouse BV-2 microglial cells. Similarly, MBP-primed T cells also induced the production of NO in mouse primary microglia. This induction of NO production was primarily dependent on the contact between MBP-primed T cells and microglia. The expression of very late antigen-4 (VLA-4) on the surface of MBP-primed T cells and inhibition of MBP-primed T cell-induced microglial NO production by functional blocking of antibodies to the alpha(4) chain of VLA-4 (CD49d) suggest that VLA-4 integrin on MBP-primed T cells plays an important role in contact-mediated induction of iNOS. Since IFN-beta has been used to treat MS patients, we examined the effect of IFN-beta on MBP-primed T cell-induced the production of NO. Surprisingly, IFN-beta alone induced the production of NO in microglial cells. However, the pretreatment of MBP-primed T cells with IFN-beta inhibited the expression of VLA-4 integrin on the surface of MBP-primed T cells and thereby inhibited the ability of those T cells to induce the production of NO in microglial cells. This study illustrates a novel role of neuroantigen-primed T cells in inducing contact-mediated expression of iNOS in microglial cells that may participate in the pathogenesis of MS.
Highlights
Nitric oxide (NO),1 a short-lived and bioactive free radical, has been recognized to have many functions in normal physiological and pathophysiological conditions (1, 2)
Since NO produced in excessive amount from the activation of inducible nitric oxide synthase (iNOS) participates in the pathogenesis of multiple sclerosis (MS), we investigated the role of neuroantigen-specific T cells in the expression of iNOS in microglial cells
myelin basic protein (MBP)-primed T Cells Induce the Production of NO and the Expression of iNOS in BV-2 Microglial Cells—T cells isolated from lymph nodes of MBP-primed mice proliferated in response to MBP, and maximum proliferation was observed at 50 or 100 g/ml MBP (Fig. 1)
Summary
Nitric oxide (NO), a short-lived and bioactive free radical, has been recognized to have many functions in normal physiological and pathophysiological conditions (1, 2). Uric acid, a scavenger of peroxynitrite, markedly inhibits the appearance of EAE in mice, and the incidence of MS has been found very rare among gout patients having higher levels of uric acid, suggesting the critical involvement of peroxynitrite in the disease process of EAE and MS. The mechanisms through which neuroantigen-specific T cells play an etiologic role in MS remain unclear. Since NO produced in excessive amount from the activation of iNOS participates in the pathogenesis of MS, we investigated the role of neuroantigen-specific T cells in the expression of iNOS in microglial cells. We report that MBP-primed T cells induce the expression of iNOS in mouse microglial cells through cell-cell contact and that very late antigen-4 (VLA-4) on the T cell surface plays an important role in this process. Interferon- (IFN-) inhibited the expression of VLA-4 and thereby blocked the ability of MBP-primed T cells to induce microglial iNOS
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