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A Dual Role for REV-ERBa in Th17 Cell Mediated Immune Response


T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis(Korn, Bettelli, Oukka, & Kuchroo, 2009; Weaver, Hatton, Mangan, & Harrington, 2007). The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORgt(Ivanov et al., 2006). Here we identify REV-ERBa (encoded by Nr1d1), a member of the nuclear hormone receptor (NHR) family, as a transcriptional repressor that antagonizes RORgt function in Th17 cells.

REV-ERBa binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORgt-dependent genes including Il17a and Il17f. Furthermore, elevated REV-ERBa expression or treatment with a synthetic REV- ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE), a Th17 cell-mediated autoimmune disease. These results suggest that modulating REV-ERBa activity may hold therapeutic potential for treatment of Th17 cell-mediated autoimmune diseases.

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