Hypoxia/reoxygenation-induced HMGBI translocation and release promotes islet proinflammatory cytokine production and early islet graft failure through TLRs signaling
Hypoxia/reoxygenation-induced HMGBI translocation and release promotes islet proinflammatory cytokine production and early islet graft failure through TLRs signaling
复制标题
缺氧/复氧诱导的 HMGB1 易位和释放通过 TLR 信号传导促进胰岛促炎细胞因子的产生和早期胰岛移植失败。
DOI：
10.1016/j.bbadis.2016.11.012
复制
发表时间：
2017-02-01
影响因子：
6.2
通讯作者：
He, Sirong
中科院分区：
文献类型：
--
作者：
Cheng, Yao;Xiong, Junjie;He, Sirong
高迁移率族蛋白 1 (HMGB1) 易位和释放参与多种组织类型的缺血再灌注损伤，通过与 Toll 样受体 (TLR) 的相互作用诱导促炎细胞因子的产生，从而激活先天免疫。我们的目的是确定 HMGB1 的作用以及 TLR 相关信号转导通路在缺氧/复氧 (H/R) 诱导的促炎细胞因子产生和胰岛移植物炎症中的激活程度。胰岛缺氧复氧24 h后，胰岛中TLR2/4表达和TLR介导的信号上调，HMGB1从细胞核易位到细胞质并释放到细胞外空间。随着 H/R 暴露，促炎细胞因子的产生（1-1β 和 TNF-α）和胰岛损伤显着增加，这些效应取决于 TLR2/4 信号通路。外源 HMGB1 还会诱导胰岛炎症并增加野生型胰岛中 STAT3、p38 和 I kappa B α 的磷酸化。 TLR2-KO 胰岛中的 TLR2 缺陷导致 HMGB1 暴露后 IL-1 β 产生和 STAT3/p38 磷酸化受到抑制。 TLR4-KO 胰岛中的 TLR4 缺陷导致 HMGB1 暴露后 TNF-α 产生和 IκB α 磷酸化受到抑制。预孵育 STAT3、p38 或 NF-κ B 抑制剂可显着抑制 HMGB1 诱导的胰岛中 IL-1 β 或 TNF-α 的产生，但 STAT3 抑制剂、p38 抑制剂或 NF-κ B 抑制剂的单独治疗不能抵消 HMGB1 或 H/R 诱导的胰岛损伤的影响。丙酮酸乙酯抑制 HMGB1 或中和抗体阻断可显着降低 STAT3、p38 和 I kappa B α 的磷酸化、IL-1 β 和 TNF-α 的产生以及暴露于 H/R 后野生型胰岛的胰岛损伤，并显着改善早期胰岛移植失败。因此，我们的结果表明，从 H/R 诱导的胰岛释放的 HMGB1 以自分泌方式发挥作用，上调 STAT 或 p38，并通过 TLR2 增加 IL-1 β 的产生，并上调 NF-κ B 并通过胰岛内的 TLR4 增加 TNF-α 的产生，这与 H/R 诱导的胰岛损伤和早期移植失败有关。 (C) 2016 Elsevier B.V. 保留所有权利。
High-mobility group box 1 (HMGB1) translocation and release, which is involved in several tissue types of ischemia-reperfusion injuries, activate innate immunity by inducing proinflammatory cytokine production through its interaction with toll-like receptors (TLRs). Our objective was to determine the role of HMGB1 and the degree of activation of TLR-related signal transduction pathways in hypoxia/reoxygenation (H/R)-induced proinflammatory cytokine production and intra-islet graft inflammation. After islets are exposed to hypoxia-reoxygenation for 24 h, TLR2/4 expression and TLR-mediated signaling was up-regulated in islets, and HMGB1 was translocated from the nucleus to the cytoplasm and released to the extracellular space. With H/R exposure, proinflammatory cytokine production (1-1 beta and TNF-alpha) and islet injury were significantly increased, and these effects depend on TLR2/4 signaling pathways. Exogenous HMGB1 also induces islet inflammation and increases the phosphorylation of STAT3, p38 and I kappa B alpha in wild-type islets. TLR2 deficiency in TLR2-KO islets resulted in the inhibition of IL-1 beta production and STAT3/p38 phosphorylation after HMGB1 exposure. TLR4 deficiency in TLR4-KO islets resulted in the inhibition of TNF-alpha production and I kappa B alpha phosphorylation after HMGB1 exposure. Pre-incubation of the STAT3, p38, or NF-kappa B inhibitors significantly inhibited HMGB1-induced IL-1 beta or TNF-alpha production in islets, but the effect of HMGB1 or H/R-induced islet injury was not counteracted by a separate treatment of the STAT3 inhibitor, p38 inhibitor, or NF-kappa B inhibitors. HMGB1 inhibition by ethyl pyruvate or blockade by neutralizing antibodies significantly decreased the phosphorylation of STAT3, p38 and I kappa B alpha, the production of IL-1 beta and TNF-alpha, and the islet injury in wild-type islets after exposure to H/R and significantly improved early islet graft failure. Thus, our results suggest that HMGB1 released from H/R induced islets works in an autocrine manner to up-regulate STAT or p38 and augment IL-1 beta production via TLR2, and up-regulate NF-kappa B and augment TNF-alpha production via TLR4 in intra-islet, which are associated with H/R-induced islet injury and early graft failure. (C) 2016 Elsevier B.V. All rights reserved.