Abstract
Although 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / immunology
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Animals
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Antibodies, Monoclonal / pharmacology
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B-Lymphocytes / drug effects
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B-Lymphocytes / immunology*
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B-Lymphocytes / pathology
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Cell Differentiation
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Disease Models, Animal
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Female
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Gene Expression Regulation
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Interleukins / antagonists & inhibitors
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Interleukins / genetics*
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Interleukins / immunology
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Leukocytes, Mononuclear / drug effects
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Leukocytes, Mononuclear / immunology
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Leukocytes, Mononuclear / pathology
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Lupus Erythematosus, Systemic / drug therapy
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Lupus Erythematosus, Systemic / genetics*
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Primary Cell Culture
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Receptors, Interleukin / deficiency
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Receptors, Interleukin / genetics
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Receptors, Interleukin / immunology
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Receptors, Interleukin-17 / deficiency
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Receptors, Interleukin-17 / genetics
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Receptors, Interleukin-17 / immunology
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STAT3 Transcription Factor / genetics*
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STAT3 Transcription Factor / immunology
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Signal Transduction
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Sjogren's Syndrome / drug therapy
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Sjogren's Syndrome / genetics*
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Sjogren's Syndrome / immunology
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Sjogren's Syndrome / pathology
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Spleen
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology*
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T-Lymphocytes / pathology
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Monoclonal
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Il17a protein, mouse
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Il17ra protein, mouse
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Il17rb protein, mouse
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Il17rc protein, mouse
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Interleukin-17
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Interleukins
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Receptors, Interleukin
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Receptors, Interleukin-17
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Traf3ip2 protein, mouse
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interleukin-23 receptor, mouse
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interleukin-21