T helper cells that produce Interleukin-17 (IL-17) (TH17 cells) are a recently identified CD4+ T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors α and γt (RORα and RORγt, respectively) are required for the full differentiation of naïve CD4+ T cells into TH17 cells. SR-1001 is an inverse agonist ligand of RORα/RORγ which dose dependently displaces [3H]25-hydroxycholesterol binding to RORα and RORγ (Ki = 172 and 111 nM, respectively). In HEK293 cells, SR-1001 repressed both GAL4-RORα and GAL4-RORγ transcriptional activity in a dose dependent manner. Also in HEK293 cells transfected with the Il17 reporter and either full-length RORα or RORγ, SR-1001 dose-dependently suppressed the Il17 promoter driven activity by each of the receptors. In EL4 cells expressing RORα, RORγt and IL-17A (Il17α), treatment of cells with SR-1001 suppressed Il17α mRNA expression indicating that SR-1001 suppression of Il17α mRNA expression is RORα/RORγ dependent. In an animal model of TS17 cell-mediated autoimmune disease, 25 mg/kg of SR-1001 b.i.d. i.p. delayed the onset and clinical severity of EAE (experimental autoimmune encephalomyelitis)[3].
作用机制
SR-1001 binds specifically to the ligand binding domains (LBDs) of RORα and RORγt inducing a conformational change within the LBD[3].
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