scholarly journals Mechanism of Transforming Growth Factor β–induced Inhibition of T Helper Type 1 Differentiation

2002 ◽  
Vol 195 (11) ◽  
pp. 1499-1505 ◽  
Author(s):  
Leonid Gorelik ◽  
Stephanie Constant ◽  
Richard A. Flavell
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Interleukin 12 ◽  
T Helper ◽  
Retroviral Transduction ◽  
Cell Functions ◽  
Proliferation And Differentiation ◽  
Direct Inhibitory Effect

Regulation by transforming growth factor (TGF)-β plays an important role in immune homeostasis. TGF-β inhibits T cell functions by blocking both proliferation and differentiation. Here we show that TGF-β blocks Th1 differentiation by inhibiting the expression of T-bet, the apparent masterregulator of T helper (Th)1 differentiation. Restoration of T-bet expression through retroviral transduction of T-bet into developing Th1 cells abrogated the inhibitory effect of TGF-β. In addition, we show that, contrary to prior suggestions, downregulation of interleukin 12 receptor β2 chain is not key to the TGF-β–mediated effect. Furthermore, we show that the direct inhibitory effect of TGF-β on T cells is responsible, at least in part, for the inability of BALB/c mice to mount a Leishmania-specific Th1 response and to clear Leishmanial infection.

Downregulation of Interleukin-12 (IL-12) Responsiveness in Human T Cells by Transforming Growth Factor-β: Relationship With IL-12 Signaling

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1448-1455 ◽  
Author(s):  
Cécile Pardoux ◽  
Xiaojing Ma ◽  
Stéphanie Gobert ◽  
Sandra Pellegrini ◽  
Patrick Mayeux ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Mobility Shift ◽  
Activated T Cells ◽  
Biochemical Basis

Interleukin-12 (IL-12) is a cytokine that plays a central role in the control of cell-mediated immunity. We have previously shown that transforming growth factor-β1 (TGF-β) inhibitory effects on human primary allogeneic cytotoxicity and proliferative responses interfere with IL-12 pathway. The present study was undertaken to further elucidate the biochemical basis of the functional interaction between these two cytokines and to define the site of TGF-β action on the signaling pathway activated by IL-12. Our data indicate that TGF-β induced an inhibition of interferon-γ (IFN-γ) production without affecting the IL-12Rβ1 and IL-12Rβ2 subunits mRNA expression by activated T cells. We further show that TGF-β has a significant inhibitory effect on the early signal transduction events following interaction of IL-12 with its receptor on activated T cells, resulting in the inhibition of both JAK2 and Tyk2 phosphorylation. In addition, TGF-β was found to significantly inhibit IL-12–induced phosphorylation of the STAT4 transcription factor. Electrophoretic mobility shift assay indicated that TGF-β induced a decrease in IL-12–induced STAT4 DNA binding activity in T lymphocytes. This study suggests that TGF-β influences IL-12 responsiveness at least in part by inhibiting early signaling events essential to gene induction in IL-12–activated T cells.

Downregulation of Interleukin-12 (IL-12) Responsiveness in Human T Cells by Transforming Growth Factor-β: Relationship With IL-12 Signaling

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1448-1455 ◽  
Author(s):  
Cécile Pardoux ◽  
Xiaojing Ma ◽  
Stéphanie Gobert ◽  
Sandra Pellegrini ◽  
Patrick Mayeux ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Interleukin 12 ◽  
Cell Mediated Immunity ◽  
Mobility Shift ◽  
Activated T Cells ◽  
Biochemical Basis

Abstract Interleukin-12 (IL-12) is a cytokine that plays a central role in the control of cell-mediated immunity. We have previously shown that transforming growth factor-β1 (TGF-β) inhibitory effects on human primary allogeneic cytotoxicity and proliferative responses interfere with IL-12 pathway. The present study was undertaken to further elucidate the biochemical basis of the functional interaction between these two cytokines and to define the site of TGF-β action on the signaling pathway activated by IL-12. Our data indicate that TGF-β induced an inhibition of interferon-γ (IFN-γ) production without affecting the IL-12Rβ1 and IL-12Rβ2 subunits mRNA expression by activated T cells. We further show that TGF-β has a significant inhibitory effect on the early signal transduction events following interaction of IL-12 with its receptor on activated T cells, resulting in the inhibition of both JAK2 and Tyk2 phosphorylation. In addition, TGF-β was found to significantly inhibit IL-12–induced phosphorylation of the STAT4 transcription factor. Electrophoretic mobility shift assay indicated that TGF-β induced a decrease in IL-12–induced STAT4 DNA binding activity in T lymphocytes. This study suggests that TGF-β influences IL-12 responsiveness at least in part by inhibiting early signaling events essential to gene induction in IL-12–activated T cells.

Serum-stimulated α1 type IV collagen gene transcription is mediated by TGF-β and inhibited by estradiol

1998 ◽  
Vol 274 (2) ◽  
pp. F252-F258 ◽  
Author(s):  
Jun Lei ◽  
Sharon Silbiger ◽  
Fuad N. Ziyadeh ◽  
Joel Neugarten
Keyword(s):  
Growth Factor ◽  
Gene Transcription ◽  
Type Iv Collagen ◽  
Transforming Growth Factor ◽  
Combined Treatment ◽  
Calf Serum ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Type Iv

We examined the hypothesis that fetal calf serum (FCS) stimulates murine mesangial cell α1 type IV collagen ( COL4A1) gene transcription by increasing autocrine production of transforming growth factor-β (TGF-β) through a platelet-derived growth factor (PDGF)-dependent mechanism. PDGF-stimulated COL4A1 gene transcription was inhibited by neutralizing antibody to TGF-β (119.3 ± 3.6 vs. 106.0 ± 6.2 relative luciferase units, expressed as a percentage of control untreated cells, P < 0.003). FCS-stimulated gene transcription was inhibited by neutralizing antibody to PDGF (148.3 ± 4.1 vs. 136.7 ± 0.3 relative luciferase units, P < 0.002) and by neutralizing antibody to TGF-β (148.3 ± 4.1 vs. 127.1 ± 3.4 relative luciferase units, P < 0.036). The inhibitory effect of combined treatment with anti-PDGF and anti-TGF-β antibody on gene transcription was no greater than that of anti-TGF-β antibody alone [129.5 ± 0.53 vs. 127.1 ± 3.4 relative luciferase units, P = not significant (NS)]. FCS-stimulated gene transcription was also inhibited by estradiol (10−7 M) (148.4 ± 3.1 vs. 119.4 ± 8.1 relative luciferase units, P < 0.019). In the presence of estradiol, anti-TGF-β antibody failed to further reduce serum-stimulated gene transcription (119.4 ± 8.1 vs. 115.6 ± 9.8, P = NS), suggesting that estradiol reverses FCS-stimulated COL4A1 gene transcription by antagonizing the actions of TGF-β. Measurement of type IV collagen synthesis by Western blotting confirmed that the intact gene responded in a manner analogous to the promoter construct.

scholarly journals Transforming Growth Factor-β Signaling in Regulatory T Cells Controls T Helper-17 Cells and Tissue-Specific Immune Responses

Immunity ◽  
2017 ◽  
Vol 46 (4) ◽  
pp. 660-674 ◽  
Author(s):  
Joanne E. Konkel ◽  
Dunfang Zhang ◽  
Peter Zanvit ◽  
Cheryl Chia ◽  
Tamsin Zangarle-Murray ◽  
...  
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
T Helper ◽  
T Helper 17 ◽  
T Helper 17 Cells ◽  
Tissue Specific
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