Proceedings of the National Academy of Sciences · 2008 · 94 citations · 37 references
Life SciencesImmunologyNeuroscienceAutoimmunityGene ExpressionNeuroimmunologyCentral Nervous System ImmunityCytokine BiologyHelper T Cell SubsetsMultiple SclerosisNeuroinflammationT Cell BiologyCentral Nervous System CytokinesExperimental Autoimmune EncephalomyelitisImmune Cell Cytokine ProductionInflammatory CascadeInflammatory Cytokine ProductionInflammatory DemyelinationOrphan Nuclear ReceptorsT Cell Cytokine Production
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by Th17 and Th1 cells. DNA microarray analysis previously showed that NR4A2, an orphan nuclear receptor, is strongly up-regulated in the peripheral blood T cells of MS. Here, we report that NR4A2 plays a pivotal role for mediating cytokine production from pathogenic T cells. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, NR4A2, was selectively up-regulated in the T cells isolated from the CNS. Strikingly, a forced expression of NR4A2 augmented promoter activities of IL-17 and IFN-gamma genes, leading to an excessive production of these cytokines. Conversely, treatment with siRNA for NR4A2, resulted in a significant reduction in the production of IL-17 and IFN-gamma. Furthermore, treatment with NR4A2 siRNA reduced the ability of encephalitogenic T cells to transfer EAE in recipient mice. Thus, NR4A2 is an essential transcription factor for triggering the inflammatory cascade of MS/EAE and may serve as a therapeutic target.
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Reciprocal T <sub>H</sub> 17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid
Daniel Mucida, Yunji Park, Gisen Kim et al. · Science · 2007 · 1.9K citations