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IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4⁺ T cells.

ABSTRACT: Severe or prolonged inflammatory response caused by infection or biomaterials leads to delayed healing or bone repair failure. This study investigated the important roles of the proinflammatory cytokines of the interleukin-12 (IL-12) family, namely, IL-12 and IL-23, in the inflammation-mediated inhibition of bone formation in vivo. IL-12p40^-/- mice lacking IL-12 and IL-23 exhibited enhanced bone formation. IL-12 and IL-23 indirectly inhibited bone marrow mesenchymal stem cell (BMMSC) differentiation by stimulating CD4⁺ T cells to increase interferon γ (IFN-γ) and IL-17 levels. Mechanistically, IL-17 synergistically enhanced IFN-γ-induced BMMSC apoptosis. Moreover, INF-γ and IL-17 exerted proapoptotic effects by upregulating the expression levels of Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as well as by activating the caspase cascade in BMMSCs. IL-12p40 depletion in mice could promote ectopic bone formation. Thus, IL-12p40 is an attractive therapeutic target to overcome the inflammation-mediated inhibition of bone formation in vivo.

SUBMITTER: Xu J

PROVIDER: S-EPMC5136484 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4<sup>+</sup> T cells.

Xu Jiajia J Wang Yiyun Y Li Jing J Zhang Xudong X Geng Yiyun Y Huang Yan Y Dai Kerong K Zhang Xiaoling X

Cell death and differentiation 20160729 12

Severe or prolonged inflammatory response caused by infection or biomaterials leads to delayed healing or bone repair failure. This study investigated the important roles of the proinflammatory cytokines of the interleukin-12 (IL-12) family, namely, IL-12 and IL-23, in the inflammation-mediated inhibition of bone formation in vivo. IL-12p40<sup>-/-</sup> mice lacking IL-12 and IL-23 exhibited enhanced bone formation. IL-12 and IL-23 indirectly inhibited bone marrow mesenchymal stem cell (BMMSC) ...[more]

PMID: 27472064

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Project description:BackgroundMesenchymal stem cells (MSCs) have been recognized as a promising tool for the treatment of various inflammatory disorders and autoimmune diseases. Stress conditions affect immune-mediated treatment and activate autophagy in MSCs. However, whether autophagy affects the MSC-mediated recruitment and differentiation of CD4+ T cells remains elusive.MethodsMSCs were pretreated with 3-methyladenine (3-MA) and rapamycin to regulate autophagy, and then co-cultured with CD4+ T cells. CD4+ T cell migration and differentiation were detected by flow cytometry. Further, gene expression levels of well-known chemokines were analyzed by quantitative real-time PCR. Enzyme-linked immunosorbent assays and western blot analysis were performed to detect C-X-C motif chemokine ligand 8 (CXCL8) and transforming growth factor (TGF)-β1 protein levels. An exogenous antibody and short hairpin RNA were used to regulate CXCL8 and TGF-β1 levels, which enabled us to evaluate how autophagy affected MSC-mediated CD4+ T cell migration and differentiation.Results3-MA inhibited autophagy in MSCs, which was activated by rapamycin. Rapamycin increased the migration of CD4+ T cells, whereas 3-MA decreased their migration. Mechanistically, we found that autophagy strengthened CXCL8 secretion, and the addition of exogenous CXCL8 and an anti-CXCL8 antibody eliminated the difference of CD4+ T cell migration among groups. Further, the ratio of regulatory T (Treg) cells was increased in rapamycin-pretreated MSCs, but the ratio of T helper 1 (Th1) cells was decreased, while pretreatment of MSCs with 3-MA induced the opposite effect compared with the control group. TGF-β1 overexpression and knockdown using lentiviruses rectified the differences in the ratios of Treg and Th1 cells among the groups.ConclusionThis study demonstrates that autophagy of mesenchymal stem cells mediates CD4+ T cell migration and differentiation through CXCL8 and TGF-β1, respectively. These results provide a potential new strategy for improving MSC-mediated therapy.

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IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4⁺ T cells.

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IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4<sup>+</sup> T cells.

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IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4+ T cells.

Publications

IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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IL-12p40 impairs mesenchymal stem cell-mediated bone regeneration via CD4⁺ T cells.