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- Title
Act1 is a negative regulator in T and B cells via direct inhibition of STAT3.
- Authors
Cun-Jin Zhang; Chenhui Wang; Meiling Jiang; Chunfang Gu; Jianxin Xiao; Xing Chen; Martin, Bradley N.; Fangqiang Tang; Yamamoto, Erin; Yibo Xian; Han Wang; Fengling Li; Sartor, R. Balfour; Smith, Howard; Husni, M. Elaine; Fu-Dong Shi; Ji Gao; Carman, Julie; Dongre, Ashok; McKarns, Susan C.
- Abstract
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 Sjögren'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 ll17rb) results in hyper IL-23- and IL-21-induced STAT3 activation in T and B cells, respectively. IL-23R deletion or blockade of IL-21 ameliorates SLE- and Sjögren'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, anti-IL-21 ameliorates the SLE- and Sjögren's-like diseases in Act1-deficient mice. Thus, IL-21 blocking antibody might be an effective therapy for treating SLE- and Sjögren's-like syndrome in patients containing Act1 mutation.
- Publication
Nature Communications, 2018, Vol 9, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-018-04974-3