Hasan, Maruf and Neumann, Bernhard and Haupeltshofer, Steffen and Stahlke, Sarah and Fantini, Massimo Claudio and Angstwurm, Klemens and Bogdahn, Ulrich and Kleiter, Ingo (2015) Activation of TGF-beta-induced non-Smad signaling pathways during Th17 differentiation. IMMUNOLOGY AND CELL BIOLOGY, 93 (7). pp. 662-672. ISSN 0818-9641, 1440-1711
Full text not available from this repository. (Request a copy)Abstract
Although transforming growth factor-beta (TGF-beta) has been shown to positively regulate the development of murine T helper type 17 (Th17) cells, which of the intracellular signaling pathways are involved is controversial. We examined Smad-dependent and -independent signaling molecules downstream of the TGF-beta receptor (TGF beta R) involved in Th17 differentiation of naive murine CD4(+)CD62L(+) T cells. During Th17 differentiation of wild-type T cells, Smad2/3 was phosphorylated, indicating activation of the canonical Smad pathway. T cells lacking TGF beta RII did not differentiate into Th17, whereas T cells treated with a TGF beta RI kinase inhibitor (SB-431542) or overexpression of inhibitory Smad7 retained a low amount of Th17 polarization despite absent Smad2/3 phosphorylation. Using protein antibody arrays we found an increase of expression and phosphorylation of the following Smad-independent signaling molecules in Th17-polarized wild-type T cells: AKT1(Tyr474), AKT2 (Ser474), ERK1-p44/42 MAPK (Tyr204), mTOR(Thr2446), p38 MAPK(Thr180), Rac1/cdc42(Ser71), SAPK/JNK(Tyr185) and SP1(Thr739). Pharmacological inhibition of AKT/mammalian target of rapamycin (mTOR) signaling with rapamycin or LY294002 decreased Th17 differentiation of wild-type T cells, and completely abolished interleukin-17 production in T cells with overexpression of Smad7. Rapamycin and LY294002 also decreased induced regulatory T cell differentiation, but only had minor additive effects to Smad7 overexpression. Finally, inhibitors of mitogen-activated protein kinase (MAPK) blocked in vitro polarization of Th17 cells. Our data show that Smad-dependent and -independent intracellular pathways contribute to murine Th17 differentiation.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | GROWTH-FACTOR-BETA; REGULATORY T-CELLS; GENERATION; INDUCTION; T(H)17; IL-17; TRANSCRIPTION; INACTIVATION; INFLAMMATION; PLASTICITY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Neurologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Jun 2019 13:53 |
| Last Modified: | 25 Jun 2019 13:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5122 |
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