Induction of nitric oxide synthase in microglial cells by MBP‐primed T cells

Abstract

The present study was undertaken to investigate the role of MBP‐primed T cells in the expression of 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. This induction of NO production was primarily dependent on the contact between MBP‐primed T cells and microglia. Similarly, MBP‐primed T cells also induced the contact‐mediated production of NO in mouse primary microglia. To understand the mechanism of induction of iNOS, we investigated the role of NF‐κB, transcription factor responsible for the induction of iNOS. MBP‐primed T cells alone were able to induce the activation of NF‐κB. Consistently, Dp65, a dominant‐negative mutant of p65, and SN50, a specific inhibitor of p50 NF‐κB, but not SN50M, a nonfunctional peptide mutant, inhibited MBP‐primed T cell‐induced production of NO in BV‐2 microglial cells suggesting that MBP‐primed T cell‐microglia contact induces the expression of iNOS through the activation of NF‐κB. Since IFN‐β has been used to treat MS patients, we examined the effect of IFN‐β on T cell‐mediated production of NO and activation of NF‐κB. Surprisingly, IFN‐β alone induced the production of NO and the activation NF‐κB in microglial cells. However, the pretreatment of MBP‐primed T cells with IFN‐β markedly inhibited the ability of MBP‐primed T cells to induce the production of NO and the activation NF‐κB in microglial cells, mechanisms which can help account for its efficacy in MS.Acknowledgements: This study was supported by NIH grants (NS39940 and AG19487).