Myelin basic protein-primed T cells of female but not male mice induce nitric-oxide synthase and proinflammatory cytokines in microglia - Implications for gender bias in multiple sclerosis

Females are more susceptible than males to multiple sclerosis ( MS). However, the underlying mechanism behind this gender difference is poorly understood. Because the presence of neuroantigen- primed T cells within the CNS is necessary for the development of MS, the present study was undertaken to investigate the activation of microglia by myelin basic protein ( MBP)- primed T cells of male, female, and castrated male mice. Interestingly, MBP- primed T cells isolated from female and castrated male but not from male mice induced the expression of inducible nitric- oxide synthase ( iNOS) and proinflammatory cytokines ( interleukin- 1 beta ( IL- 1 beta), IL- 1 alpha, IL- 6, and tumor necrosis factor- alpha) in microglia by cell- cell contact. Again there was no apparent defect in male microglia, because MBP- primed T cells isolated from female and castrated male but not male mice were capable of inducing the production of NO in male primary microglia. Inhibition of female T cell contact- mediated microglial expression of proinflammatory molecules by dominant- negative mutants of p65 and C/ EBP beta suggest that female MBP- primed T cells induce microglial expression of proinflammatory molecules through the activation of NF- kappa B and C/ EBP beta. Interestingly, MBP- primed T cells of male, female, and castrated male mice were able to induce microglial activation of NF- kappa B. However, MBP- primed T cells of female and castrated male but not male mice induced microglial activation of C/ EBP beta. These studies suggest that microglial activation of C/ EBP beta but not NF- kappa B by T cell: microglial contact is a gender- specific event and that male MBP- primed T cells are not capable of inducing microglial expression of proinflammatory molecules due to their inability to induce the activation of C/ EBP beta in microglia. This novel gender- sensitive activation of microglia by neuroantigen- primed T cell contact could be one of the mechanisms behind the female- loving nature of MS.