Act1 is a negative regulator in T and B cells via direct inhibition of STAT3
Copyright policy )Act1 is a negative regulator in T and B cells via direct inhibition of STAT3
AbstractAlthough Act1 (adaptor for IL-17 receptors) is necessary for IL-17-mediated inflammatory responses, Act1- (but not Il17ra-, Il17rc-, or Il17rb-) 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 Il17ra-, Il17rc-, or Il17rb) 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.
- Capital University United States
- PEKING UNION MEDICAL COLLEGE China (People's Republic of)
- National Institute of Health Pakistan
- University of Missouri United States
- Bristol-Myers Squibb (United States) United States
STAT3 Transcription Factor, Science, Primary Cell Culture, Article, Mice, Animals, Lupus Erythematosus, Systemic, Adaptor Proteins, Signal Transducing, Mice, Knockout, B-Lymphocytes, Receptors, Interleukin-17, Interleukins, Q, Interleukin-17, Antibodies, Monoclonal, Cell Differentiation, Receptors, Interleukin, Mice, Inbred C57BL, Disease Models, Animal, Gene Expression Regulation, Leukocytes, Mononuclear, Female, Signal Transduction
STAT3 Transcription Factor, Science, Primary Cell Culture, Article, Mice, Animals, Lupus Erythematosus, Systemic, Adaptor Proteins, Signal Transducing, Mice, Knockout, B-Lymphocytes, Receptors, Interleukin-17, Interleukins, Q, Interleukin-17, Antibodies, Monoclonal, Cell Differentiation, Receptors, Interleukin, Mice, Inbred C57BL, Disease Models, Animal, Gene Expression Regulation, Leukocytes, Mononuclear, Female, Signal Transduction
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