The Experts below are selected from a list of 199401 Experts worldwide ranked by ideXlab platform
Jonathan S Serody - One of the best experts on this subject based on the ideXlab platform.
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reversing ski smad4 mediated suppression is essential for Th17 Cell differentiation
Nature, 2017Co-Authors: Song Zhang, Wei Chun Chou, Seddon Y. Thomas, Motoki Takaku, Jonathan S Serody, Qing Kong, Ge Zhang, Liyun Zou, Xian ChenAbstract:T helper 17 (Th17) Cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in Th17 Cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables Th17 Cell differentiation remains elusive. Here we reveal that TGFβ enables Th17 Cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T Cells, SMAD4-deficient T Cells differentiate into Th17 Cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and Th17 Cell differentiation of SMAD4-deficient T Cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and Th17 Cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and Th17 Cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable Th17 Cell differentiation. This study reveals a critical mechanism by which TGFβ controls Th17 Cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating Th17-related diseases.
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Reversing SKI-SMAD4-mediated suppression is essential for Th17 Cell differentiation.
Nature, 2017Co-Authors: Song Zhang, Wei Chun Chou, Seddon Y. Thomas, Motoki Takaku, Qing Kong, Ge Zhang, Bing Wu, Jonathan S SerodyAbstract:TGFβ signalling regulates T helper 17 (Th17) Cell differentiation by reversing SKI–SMAD4-mediated suppression of RORγt, revealing a potential therapeutic target for treating Th17-related diseases. Yisong Wan and colleagues describe a novel mechanism by which transforming growth factor beta (TGFβ) regulates differentiation of T helper 17 (Th17) Cells. TGFβ and interleukin-6 (IL-6) are required for induction of the master transcription factor RORγt, but too much TGFβ is inhibitory. In this study the authors show that SMAD4—a key signal transducer activated by TGFβ receptor ligation—forms a complex with the transcriptional repressor SKI, and together they suppress transactivation of RORγt and Th17 Cell differentiation. T helper 17 (Th17) Cells are critically involved in host defence, inflammation, and autoimmunity1,2,3,4,5. Transforming growth factor β (TGFβ) is instrumental in Th17 Cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables Th17 Cell differentiation remains elusive. Here we reveal that TGFβ enables Th17 Cell differentiation by reversing SKI–SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T Cells, SMAD4-deficient T Cells differentiate into Th17 Cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and Th17 Cell differentiation of SMAD4-deficient T Cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and Th17 Cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and Th17 Cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI–SMAD4-mediated suppression of RORγt to enable Th17 Cell differentiation. This study reveals a critical mechanism by which TGFβ controls Th17 Cell differentiation and uncovers the SKI–SMAD4 axis as a potential therapeutic target for treating Th17-related diseases.
Ge Zhang - One of the best experts on this subject based on the ideXlab platform.
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reversing ski smad4 mediated suppression is essential for Th17 Cell differentiation
Nature, 2017Co-Authors: Song Zhang, Wei Chun Chou, Seddon Y. Thomas, Motoki Takaku, Jonathan S Serody, Qing Kong, Ge Zhang, Liyun Zou, Xian ChenAbstract:T helper 17 (Th17) Cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in Th17 Cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables Th17 Cell differentiation remains elusive. Here we reveal that TGFβ enables Th17 Cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T Cells, SMAD4-deficient T Cells differentiate into Th17 Cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and Th17 Cell differentiation of SMAD4-deficient T Cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and Th17 Cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and Th17 Cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable Th17 Cell differentiation. This study reveals a critical mechanism by which TGFβ controls Th17 Cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating Th17-related diseases.
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Reversing SKI-SMAD4-mediated suppression is essential for Th17 Cell differentiation.
Nature, 2017Co-Authors: Song Zhang, Wei Chun Chou, Seddon Y. Thomas, Motoki Takaku, Qing Kong, Ge Zhang, Bing Wu, Jonathan S SerodyAbstract:TGFβ signalling regulates T helper 17 (Th17) Cell differentiation by reversing SKI–SMAD4-mediated suppression of RORγt, revealing a potential therapeutic target for treating Th17-related diseases. Yisong Wan and colleagues describe a novel mechanism by which transforming growth factor beta (TGFβ) regulates differentiation of T helper 17 (Th17) Cells. TGFβ and interleukin-6 (IL-6) are required for induction of the master transcription factor RORγt, but too much TGFβ is inhibitory. In this study the authors show that SMAD4—a key signal transducer activated by TGFβ receptor ligation—forms a complex with the transcriptional repressor SKI, and together they suppress transactivation of RORγt and Th17 Cell differentiation. T helper 17 (Th17) Cells are critically involved in host defence, inflammation, and autoimmunity1,2,3,4,5. Transforming growth factor β (TGFβ) is instrumental in Th17 Cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables Th17 Cell differentiation remains elusive. Here we reveal that TGFβ enables Th17 Cell differentiation by reversing SKI–SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T Cells, SMAD4-deficient T Cells differentiate into Th17 Cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and Th17 Cell differentiation of SMAD4-deficient T Cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and Th17 Cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and Th17 Cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI–SMAD4-mediated suppression of RORγt to enable Th17 Cell differentiation. This study reveals a critical mechanism by which TGFβ controls Th17 Cell differentiation and uncovers the SKI–SMAD4 axis as a potential therapeutic target for treating Th17-related diseases.
Song Zhang - One of the best experts on this subject based on the ideXlab platform.
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reversing ski smad4 mediated suppression is essential for Th17 Cell differentiation
Nature, 2017Co-Authors: Song Zhang, Wei Chun Chou, Seddon Y. Thomas, Motoki Takaku, Jonathan S Serody, Qing Kong, Ge Zhang, Liyun Zou, Xian ChenAbstract:T helper 17 (Th17) Cells are critically involved in host defence, inflammation, and autoimmunity. Transforming growth factor β (TGFβ) is instrumental in Th17 Cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables Th17 Cell differentiation remains elusive. Here we reveal that TGFβ enables Th17 Cell differentiation by reversing SKI-SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T Cells, SMAD4-deficient T Cells differentiate into Th17 Cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and Th17 Cell differentiation of SMAD4-deficient T Cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and Th17 Cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and Th17 Cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI-SMAD4-mediated suppression of RORγt to enable Th17 Cell differentiation. This study reveals a critical mechanism by which TGFβ controls Th17 Cell differentiation and uncovers the SKI-SMAD4 axis as a potential therapeutic target for treating Th17-related diseases.
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Reversing SKI-SMAD4-mediated suppression is essential for Th17 Cell differentiation.
Nature, 2017Co-Authors: Song Zhang, Wei Chun Chou, Seddon Y. Thomas, Motoki Takaku, Qing Kong, Ge Zhang, Bing Wu, Jonathan S SerodyAbstract:TGFβ signalling regulates T helper 17 (Th17) Cell differentiation by reversing SKI–SMAD4-mediated suppression of RORγt, revealing a potential therapeutic target for treating Th17-related diseases. Yisong Wan and colleagues describe a novel mechanism by which transforming growth factor beta (TGFβ) regulates differentiation of T helper 17 (Th17) Cells. TGFβ and interleukin-6 (IL-6) are required for induction of the master transcription factor RORγt, but too much TGFβ is inhibitory. In this study the authors show that SMAD4—a key signal transducer activated by TGFβ receptor ligation—forms a complex with the transcriptional repressor SKI, and together they suppress transactivation of RORγt and Th17 Cell differentiation. T helper 17 (Th17) Cells are critically involved in host defence, inflammation, and autoimmunity1,2,3,4,5. Transforming growth factor β (TGFβ) is instrumental in Th17 Cell differentiation by cooperating with interleukin-6 (refs 6, 7). Yet, the mechanism by which TGFβ enables Th17 Cell differentiation remains elusive. Here we reveal that TGFβ enables Th17 Cell differentiation by reversing SKI–SMAD4-mediated suppression of the expression of the retinoic acid receptor (RAR)-related orphan receptor γt (RORγt). We found that, unlike wild-type T Cells, SMAD4-deficient T Cells differentiate into Th17 Cells in the absence of TGFβ signalling in a RORγt-dependent manner. Ectopic SMAD4 expression suppresses RORγt expression and Th17 Cell differentiation of SMAD4-deficient T Cells. However, TGFβ neutralizes SMAD4-mediated suppression without affecting SMAD4 binding to the Rorc locus. Proteomic analysis revealed that SMAD4 interacts with SKI, a transcriptional repressor that is degraded upon TGFβ stimulation. SKI controls histone acetylation and deacetylation of the Rorc locus and Th17 Cell differentiation via SMAD4: ectopic SKI expression inhibits H3K9 acetylation of the Rorc locus, Rorc expression, and Th17 Cell differentiation in a SMAD4-dependent manner. Therefore, TGFβ-induced disruption of SKI reverses SKI–SMAD4-mediated suppression of RORγt to enable Th17 Cell differentiation. This study reveals a critical mechanism by which TGFβ controls Th17 Cell differentiation and uncovers the SKI–SMAD4 axis as a potential therapeutic target for treating Th17-related diseases.
Richard A Flavell - One of the best experts on this subject based on the ideXlab platform.
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autocrine transforming growth factor β1 promotes in vivo Th17 Cell differentiation
Immunity, 2011Co-Authors: Ilona Gutcher, Moses Donkor, Alexander Y Rudensky, Richard A FlavellAbstract:TGF-β1 is a regulatory cytokine that has an important role in controlling T Cell differentiation. T Cell-produced TGF-β1 acts on T Cells to promote Th17 Cell differentiation and the development of experimental autoimmune encephalomyelitis (EAE). However, the exact TGF-β1-producing T Cell subset required for Th17 Cell generation and its Cellular mechanism of action remain unknown. Here we showed that deletion of the Tgfb1 gene from activated T Cells and Treg Cells, but not Treg Cells alone, abrogated Th17 Cell differentiation, resulting in almost complete protection from EAE. Furthermore, differentiation of T Cells both in vitro and in vivo demonstrated that TGF-β1 was highly expressed by Th17 Cells and acted in a predominantly autocrine manner to maintain Th17 Cells in vivo. These findings reveal an essential role for activated T Cell-produced TGF-β1 in promoting the differentiation of Th17 Cells and controlling inflammatory diseases.
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t Cell produced transforming growth factor β1 controls t Cell tolerance and regulates th1 and Th17 Cell differentiation
Immunity, 2007Co-Authors: Ming O Li, Richard A FlavellAbstract:Summary TGF-β1 is a regulatory cytokine with a pleiotropic role in immune responses. TGF-β1 is widely expressed in leukocytes and stromal Cells. However, the functions of TGF-β1 expressed by specific lineages of Cells remain unknown in vivo. Here, we show that mice with a T Cell-specific deletion of the Tgfb1 gene developed lethal immunopathology in multiple organs, and this development was associated with enhanced T Cell proliferation, activation, and CD4 + T Cell differentiation into T helper 1 (Th1) and Th2 Cells. TGF-β1 produced by Foxp3-expressing regulatory T Cells was required to inhibit Th1-Cell differentiation and inflammatory-bowel disease in a transfer model. In addition, T Cell-produced TGF-β1 promoted Th17-Cell differentiation and was indispensable for the induction of experimental autoimmune encephalomyelitis. These findings reveal essential roles for T Cell-produced TGF-β1 in controlling differentiation of T helper Cells and controlling inflammatory diseases.
Yuhua Liao - One of the best experts on this subject based on the ideXlab platform.
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Coxsackievirus B3 Directly Induced Th17 Cell Differentiation by Inhibiting Nup98 Expression in Patients with Acute Viral Myocarditis.
Frontiers in Cellular and Infection Microbiology, 2016Co-Authors: Qi Long, Yuhua Liao, Yu Xie, Wei Liang, Xiang Cheng, Jing YuanAbstract:Th17 Cells play a key role in the progression of coxsackievirus B3 (CVB3)-induced acute viral myocarditis (AVMC). However, the direct effect of virus on Th17 Cell differentiation is still unknown. Recently, nucleoporin (Nup) 98 has been proved to be associated with lymphocyte differentiation. Therefore, we investigated whether Nup98 mediated Th17 Cell differentiation in AVMC. In our study, patients with AVMC and healthy controls were recruited. The results showed that CVB3 could enter into the CD4+ T Cells in AVMC patients and healthy controls. After transfecting purified CD4+ T Cells with CVB3 in vitro, the Th17 Cell frequency, IL-17 secretion, and RORγT synthesis were increased while the Nup98 levels were decreased. Furthermore, down-regulating Nup98 expression by siRNA-Nup98 in CD4+ T Cells resulted in the elevated Th17 Cell frequency and IL-17 secretion, along with enhanced levels of RORγT, dissociative p300/CBP, and acetylated Stat3. Up-regulation of Nup98 expression by pcDNA3.1-Nup98 showed the opposite effects. Our results suggested that CVB3 directly induced CD4+ T Cell differentiation into Th17 Cells by inhibiting Nup98 expression, representing a therapeutic target in AVMC.
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microrna 155 modulates treg and Th17 Cells differentiation and Th17 Cell function by targeting socs1
PLOS ONE, 2012Co-Authors: Rui Yao, Wei Liang, Yuhua LiaoAbstract:MicroRNA (miR)-155 is a critical player in both innate and adaptive immune responses. It can influence CD4+ T Cell lineage choice. To clarify the role of miR-155 in CD4+ CD25+ regulatory T (Treg)/T helper (Th)17 Cell differentiation and function, as well as the mechanism involved, we performed gain-and loss-of-function analysis by transfection pre-miR-155 and anti-miR-155 into purified CD4+ T Cells. The results showed that miR-155 positively regulated both Treg and Th17 Cell differentiation. It also induced the release of interleukin (IL)-17A by Th17 Cells, but not the release of IL-10 and transforming growth factor (TGF)-β1 by Treg Cells. Furthermore, we found that miR-155 reacted through regulating Janus kinase/signal transducer and activator of transcription (JAK/STAT) rather than TGF-β/mothers against decapentaplegic homolog (SMAD) signaling pathway in the process of Treg and Th17 Cells differentiation. This may because suppressors of cytokine signaling (SOCS)1, the important negative regulator of JAK/STAT signaling pathway, was the direct target of miR-155 in this process, but SMAD2 and SMAD5 were not. Therefore, we demonstrated that miR-155 enhanced Treg and Th17 Cells differentiation and IL-17A production by targeting SOCS1.
