title: 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.
abstract: 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-1beta (IL-1beta), IL-1alpha, 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/EBPbeta suggest that female MBP-primed T cells induce microglial expression of proinflammatory molecules through the activation of NF-kappaB and C/EBPbeta. Interestingly, MBP-primed T cells of male, female, and castrated male mice were able to induce microglial activation of NF-kappaB. However, MBP-primed T cells of female and castrated male but not male mice induced microglial activation of C/EBPbeta. These studies suggest that microglial activation of C/EBPbeta but not NF-kappaB 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/EBPbeta 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.
authors.affiliation: Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center, Lincoln, Nebraska 68583, USA.
authors.forename: Subhajit
authors.initials: S
authors.lastname: Dasgupta
authors.forename: Malabendu
authors.initials: M
authors.lastname: Jana
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Liu
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002369:Castration; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005799:Genes, Dominant; D015151:Immunoblotting; D007249:Inflammation; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009103:Multiple Sclerosis / Q000097:blood* / Q000473:pathology*; D009154:Mutation; D004676:Myelin Basic Protein / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D012737:Sex Factors; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D004676:Myelin Basic Protein; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D012313:RNA