资源环境科技发展态势分析平台

Although Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not ll17ra-, ll17rc-, or ll17rb-) deficient mice develop spontaneous SLE-and Sjogren's-like diseases. Here, we show that Act1 functions as a negative regulator in T and B cells via direct inhibition of STAT3. Mass spectrometry analysis detected an Act1-STAT3 complex, deficiency of Act1 (but not ll17ra-, ll17rc-, or II17rb) results in hyper IL23- and IL-21-induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjogren's-like diseases in Act1(-/-) mice. Act1 deficiency results in hyperactivated follicular Th17 cells with elevated IL-21 expression, which promotes T-B cell interaction for B cell expansion and antibody production. Moreover, antiIL-21 ameliorates the SLE- and Sjogren's-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjogren's-like syndrome in patients containing Act1 mutation.