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IL-1? induced HIF-1? inhibits the differentiation of human FOXP3⁺ T cells.

ABSTRACT: Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1? significantly reduced the frequency of FOXP3⁺ T cells under iTreg-polarizing conditions. Mechanistically, we show that IL-1? activated mTORC1 and downstream upregulated hypoxia inducible factor-1 (HIF-1?) expression. Using specific inhibitors, we demonstrated that both steps were critical in the deleterious effect of IL-1? on Treg differentiation. Chemical stabilization of HIF-1? by Dimethyloxalylglycine (DMOG) also significantly impaired iTreg differentiation. Interestingly, while IL-1?-treated cells exhibited only minor changes in metabolism, DMOG treatment decreased iTreg mitochondrial respiration and increased their glycolytic capacity. In conclusion, exposure to inflammatory stimuli profoundly inhibits human Treg differentiation HIF-1? dependent, suggesting that targeting HIF-1? could be a strategy to foster iTreg differentiation in an inflammatory milieu. However, IL-1? deleterious effect does not appear to be completely driven by metabolic changes. These data thus suggest that several mechanisms contribute to the regulation of iTreg differentiation, but the timing and respective requirement for each pathway vary depending on the milieu in which iTreg differentiate.

SUBMITTER: Feldhoff LM

PROVIDER: S-EPMC5428734 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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IL-1β induced HIF-1α inhibits the differentiation of human FOXP3<sup>+</sup> T cells.

Feldhoff Lea M LM Rueda Cesar M CM Moreno-Fernandez Maria E ME Sauer Johanna J Jackson Courtney M CM Chougnet Claire A CA Rupp Jan J

Scientific reports 20170328 1

Differentiation of regulatory Treg (Treg) in the periphery is critical to control inflammatory processes. Although polarization of inducible Treg (iTreg) often occurs in an inflammatory environment, the effects exerted by inflammation on human iTreg differentiation have not been extensively studied. We observed that IL-1β significantly reduced the frequency of FOXP3<sup>+</sup> T cells under iTreg-polarizing conditions. Mechanistically, we show that IL-1β activated mTORC1 and downstream upregula ...[more]

PMID: 28352109

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Project description:Osteoarthritic (OA) chondrocytes are shown to express inducible nitric oxide synthase (iNOS) which produces high concentrations of nitric oxide (NO), particularly when stimulated with proinflammatory cytokines. NO is involved in OA cartilage degradation. On the other hand, c-Jun N-terminal Kinase (JNK) pathway mediates the activation and transcription of c-Jun, which is required for interleukin-1 (IL-1)-induction of matrix metalloproteinases-13 (MMP-13) in OA pathogenesis. Therefore, the selective inhibition of iNOS and c-Jun is a promising target for treatment and prevention of OA. The purpose of the study was to investigate the inhibitory effects of pentosan polysulfate (PPS) on IL-1β-induced iNOS, c-Jun and HIF-α isoforms upregulation in canine articular chondrocytes (CACs). Primary (P0) chondrocytes were isolated and cultured from femoral head cartilages of three (3) dogs. First passage (P1) chondrocytes were preincubated with 0, 1, 5, 15 and 40 μg/mL of PPS for 4 hr before treatment with 10 ng/mL rhIL-1β for a further 8 hr. In addition, we evaluated the effects of single and multiple cytokine with or without LPS on iNOS protein induction. PPS significantly inhibited (P < 0.05) IL-1β-induced iNOS, c-Jun and HIF-1α mRNA upregulation in a dose-dependent pattern. iNOS mRNA was significantly inhibited at 15 and 40 μg/mL whereas c-Jun and HIF-1α were significantly downregulated at 5, 15 and 40 μg/mL of PPS compared to chondrocytes treated with only rhIL-1β. Intriguingly, CACs were recalcitrant to single IL-1β, TNF-α or LPS-induction of iNOS protein including to a combination of IL-1β+TNF-α, IL-1β+LPS except to TNF-α+LPS and IL-1β+TNF-α+LPS suggestive of a protective mechanism from iNOS detrimental effects on perpetuating OA. IL-1β+TNF-α+LPS-induced iNOS protein expression was significantly abrogated by PPS. We demonstrate for the first time that PPS is a novel inhibitor of IL-1β-induced iNOS, c-Jun, and HIF-1α mRNA upregulation and iNOS protein induction which may be beneficial for prevention and treatment OA.

Dataset Information

IL-1? induced HIF-1? inhibits the differentiation of human FOXP3⁺ T cells.

Publications

IL-1β induced HIF-1α inhibits the differentiation of human FOXP3<sup>+</sup> T cells.

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Dataset Information

IL-1? induced HIF-1? inhibits the differentiation of human FOXP3+ T cells.

Publications

IL-1β induced HIF-1α inhibits the differentiation of human FOXP3<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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IL-1? induced HIF-1? inhibits the differentiation of human FOXP3⁺ T cells.