Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor, a Transforming Growth Factor β Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin-2 Signaling

2016 ◽  
Vol 68 (6) ◽  
pp. 1551-1562 ◽  
Author(s):  
Jorge Postigo ◽  
Marcos Iglesias ◽  
Pilar Álvarez ◽  
Juan Jesús Augustin ◽  
Luis Buelta ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Transforming Growth Factor Β ◽  
Autoimmune Arthritis ◽  
Morphogenetic Protein ◽  
Th17 Cell Differentiation ◽  
Membrane Bound

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (13) ◽  
pp. 3157-3157 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Th17 Cell Differentiation

scholarly journals Transforming growth factor β is dispensable for the molecular orchestration of Th17 cell differentiation

2009 ◽  
Vol 206 (11) ◽  
pp. 2407-2416 ◽  
Author(s):  
Jyoti Das ◽  
Guangwen Ren ◽  
Liying Zhang ◽  
Arthur I. Roberts ◽  
Xin Zhao ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Critical Role ◽  
Th2 Cells ◽  
Th17 Cell Differentiation ◽  
Th1 And Th2

Interleukin (IL)-17–producing T helper (Th17) cells play a critical role in the pathophysiology of several autoimmune disorders. The differentiation of Th17 cells requires the simultaneous presence of an unusual combination of cytokines: IL-6, a proinflammatory cytokine, and transforming growth factor (TGF) β, an antiinflammatory cytokine. However, the molecular mechanisms by which TGF-β exerts its effects on Th17 cell differentiation remain elusive. We report that TGF-β does not directly promote Th17 cell differentiation but instead acts indirectly by blocking expression of the transcription factors signal transducer and activator of transcription (STAT) 4 and GATA-3, thus preventing Th1 and Th2 cell differentiation. In contrast, TGF-β had no effect on the expression of retinoic acid receptor–related orphan nuclear receptor γt, a Th17-specific transcription factor. Interestingly, in Stat-6−/−T-bet−/− mice, which are unable to generate Th1 and Th2 cells, IL-6 alone was sufficient to induce robust differentiation of Th17 cells, whereas TGF-β had no effect, suggesting that TGF-β is dispensable for Th17 cell development. Consequently, BALB/c Stat-6−/−T-bet−/− mice, but not wild-type BALB/c mice, were highly susceptible to the development of experimental autoimmune encephalomyelitis, which could be blocked by anti–IL-17 antibodies but not by anti–TGF-β antibodies. Collectively, these data provide evidence that TGF-β is not directly required for the molecular orchestration of Th17 cell differentiation.

scholarly journals Autocrine Transforming Growth Factor-β1 Promotes In Vivo Th17 Cell Differentiation

Immunity ◽  
2011 ◽  
Vol 34 (3) ◽  
pp. 396-408 ◽  
Author(s):  
Ilona Gutcher ◽  
Moses K. Donkor ◽  
Qian Ma ◽  
Alexander Y. Rudensky ◽  
Richard A. Flavell ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Th17 Cell ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Th17 Cell Differentiation

scholarly journals Nuclear Factor YY1 Inhibits Transforming Growth Factor β- and Bone Morphogenetic Protein-Induced Cell Differentiation

2003 ◽  
Vol 23 (13) ◽  
pp. 4494-4510 ◽  
Author(s):  
Keiko Kurisaki ◽  
Akira Kurisaki ◽  
Ulrich Valcourt ◽  
Alexei A. Terentiev ◽  
Katerina Pardali ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Growth Factor ◽  
Bone Morphogenetic Protein ◽  
Transforming Growth Factor ◽  
Immediate Early Genes ◽  
Transforming Growth Factor Β ◽  
Immediate Early ◽  
Early Genes ◽  
Morphogenetic Protein ◽  
Pai 1

ABSTRACT Smad proteins transduce transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signals that regulate cell growth and differentiation. We have identified YY1, a transcription factor that positively or negatively regulates transcription of many genes, as a novel Smad-interacting protein. YY1 represses the induction of immediate-early genes to TGF-β and BMP, such as the plasminogen activator inhibitor 1 gene (PAI-1) and the inhibitor of differentiation/inhibitor of DNA binding 1 gene (Id-1). YY1 inhibits binding of Smads to their cognate DNA elements in vitro and blocks Smad recruitment to the Smad-binding element-rich region of the PAI-1 promoter in vivo. YY1 interacts with the conserved N-terminal Mad homology 1 domain of Smad4 and to a lesser extent with Smad1, Smad2, and Smad3. The YY1 zinc finger domain mediates the association with Smads and is necessary for the repressive effect of YY1 on Smad transcriptional activity. Moreover, downregulation of endogenous YY1 by antisense and small interfering RNA strategies results in enhanced transcriptional responses to TGF-β or BMP. Ectopic expression of YY1 inhibits, while knockdown of endogenous YY1 enhances, TGF-β- and BMP-induced cell differentiation. In contrast, overexpression or knockdown of YY1 does not affect growth inhibition induced by TGF-β or BMP. Accordingly, YY1 does not interfere with the regulation of immediate-early genes involved in the TGF-β growth-inhibitory response, the cell cycle inhibitors p15 and p21, and the proto-oncogene c-myc. In conclusion, YY1 represses Smad transcriptional activities in a gene-specific manner and thus regulates cell differentiation induced by TGF-β superfamily pathways.

scholarly journals ADAM9 enhances Th17 cell differentiation and autoimmunity by activating TGF-β1

2021 ◽  
Vol 118 (18) ◽  
pp. e2023230118
Author(s):  
Masataka Umeda ◽  
Nobuya Yoshida ◽  
Ryo Hisada ◽  
Catalina Burbano ◽  
Seo Yeon K. Orite ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
Growth Factor ◽  
Lupus Erythematosus ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Th17 Cell Differentiation ◽  
Adam Family

The a disintegrin and metalloproteinase (ADAM) family of proteinases alter the extracellular environment and are involved in the development of T cells and autoimmunity. The role of ADAM family members in Th17 cell differentiation is unknown. We identified ADAM9 to be specifically expressed and to promote Th17 differentiation. Mechanistically, we found that ADAM9 cleaved the latency-associated peptide to produce bioactive transforming growth factor β1, which promoted SMAD2/3 phosphorylation and activation. A transcription factor inducible cAMP early repressor was found to bind directly to the ADAM9 promoter and to promote its transcription. Adam9-deficient mice displayed mitigated experimental autoimmune encephalomyelitis, and transfer of Adam9-deficient myelin oligodendrocyte globulin-specific T cells into Rag1−/− mice failed to induce disease. At the translational level, an increased abundance of ADAM9 levels was observed in CD4+ T cells from patients with systemic lupus erythematosus, and ADAM9 gene deletion in lupus primary CD4+ T cells clearly attenuated their ability to differentiate into Th17 cells. These findings revealed that ADAM9 as a proteinase provides Th17 cells with an ability to activate transforming growth factor β1 and accelerates its differentiation, resulting in aberrant autoimmunity.

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