Department of Respiratory, Zhongshan city people's hospital, Zhongshan, Guangdong, China.
Department of Respiratory, Inner Mongolia people's hospital, Hohhot, Inner Mongolia, China.
J Cell Biochem. 2018 May;119(5):4205-4215. doi: 10.1002/jcb.26653. Epub 2018 Jan 25.
Imbalanced T-helper (TH)1/Th2 response contributes significantly to asthma pathogenesis. Our study indicated that HMGB1 play an important role in the release of Th2-associated cytokines of asthma. However, the specific mechanism about HMGB1-induced imbalanced TH1/Th2 response is not known. In vivo, an OVA-induced asthma mouse model was set up and mice treated with anti-HMGB1 IgG. The mice treated with the anti-HMGB1 IgG ameliorated airway hyper-reactivity, disruption of Th1/Th2 balance and the upregulation of GRP75 induced by OVA. In vitro, the exposure of normal human bronchial epithelial cells to HMGB1 resulted in the upregulation of GRP75, proinflammatory cytokine production, enhanced ER-Mitochondrial Ca transfer, and enhancement of reactive oxygen species (ROS). While HMGB1-induced these changes were attenuated by GRP75 siRNA treatment. Sequentially, pretreatment with 2-APB, SKF960365 (SKF) and Ru360 which inhibit ER-Mitochondrial Ca transfer significantly lowered HMGB1-induced the generation of ROS and the release of Th2 cytokines in 16HBE cells. Meanwhile, N-acetylcysteine (NAC) significantly attenuated the HMGB1-mediated pro-inflammatory cytokines release. Therefore, these results indicate that GRP75-mediated ER-Mitochondrial Ca transfer may be an important contributor in imbalanced of Th1/Th2 balance of asthma. Moreover, HMGB1 specifically induces the release of Th2 cytokines through GRP75-mediated enhancement of ER-Mitochondrial Ca transfer and ROS increased.
失衡的辅助性 T 细胞（TH）1/TH2 反应对哮喘发病机制有重要贡献。我们的研究表明，高迁移率族蛋白 B1（HMGB1）在哮喘中 TH2 相关细胞因子的释放中起重要作用。然而，HMGB1 诱导的 TH1/TH2 失衡的具体机制尚不清楚。在体内，建立了卵清蛋白（OVA）诱导的哮喘小鼠模型，并对其给予抗 HMGB1 IgG 治疗。与对照组相比，抗 HMGB1 IgG 治疗可改善气道高反应性、TH1/TH2 失衡以及 OVA 诱导的 GRP75 上调。在体外，HMGB1 暴露于正常人支气管上皮细胞可导致 GRP75 上调、促炎细胞因子产生增加、内质网-线粒体 Ca 转移增强以及活性氧（ROS）生成增加。而 GRP75 siRNA 处理可减弱 HMGB1 诱导的这些变化。随后，用 2-APB、SKF960365（SKF）和 Ru360（抑制内质网-线粒体 Ca 转移）预处理可显著降低 HMGB1 诱导的 16HBE 细胞中 ROS 的生成和 TH2 细胞因子的释放。同时，N-乙酰半胱氨酸（NAC）可显著减弱 HMGB1 介导的促炎细胞因子释放。因此，这些结果表明，GRP75 介导的内质网-线粒体 Ca 转移可能是哮喘 TH1/TH2 失衡的一个重要因素。此外，HMGB1 可通过 GRP75 介导的内质网-线粒体 Ca 转移增强和 ROS 增加来特异性诱导 TH2 细胞因子的释放。
