Rao Zebing, Zhang Na, Xu Ning, Pan Ying, Xiao Mengjun, Wu Junxian, Zhou Hong, Yang Shuo, Chen Yunzi
Department of Immunology, Nanjing Medical University, Nanjing, China.
Key Laboratory of Antibody Techniques of Ministry of Health, Nanjing Medical University, Nanjing, China.
Front Immunol. 2017 Oct 16;8:1308. doi: 10.3389/fimmu.2017.01308. eCollection 2017.
1,25-Dihydroxyvitamin D [1,25(OH)D] is recognized as a key mediator of inflammatory diseases, including sepsis. Clinical studies demonstrate that 1,25 (OH)D protects patients from sepsis, but clinical treatment with 1,25(OH)D is rare. In this study, we report that 1,25(OH)D treatment has beneficial effects and improves the survival rate in LPS-induced mouse sepsis model by blocking the secretion of high-mobility group box 1 (HMGB1), a key late regulator of sepsis. LPS-induced HMGB1 secretion is attenuated by 1,25(OH)D blocking HMGB1 translocation from the nucleus to the cytoplasm in macrophages. 1,25(OH)D can induce the expression of hemeoxygenase-1 (HO-1), which is essential for blocking HMBG1 nuclear translocation and its secretion. When siHO-1 or an HO-1 inhibitor are used, the effect of 1,25(OH)D on inhibition of HMGB1 secretion is suppressed. Considering that HO-1 is a downstream gene of NF-E2-related factor 2 (Nrf2), we further confirm that Nrf2 activation can be activated by 1,25(OH)D upon LPS exposure. Together, we provide evidence that 1,25(OH)D attenuates LPS-induced HMGB1 secretion the Nrf2/HO-1 pathway in macrophages.
1,25-二羟基维生素D [1,25(OH)D] 被认为是包括脓毒症在内的炎症性疾病的关键介质。临床研究表明，1,25(OH)D可保护患者免受脓毒症侵害，但临床上用1,25(OH)D进行治疗的情况很少见。在本研究中，我们报告1,25(OH)D治疗具有有益作用，并通过阻断脓毒症关键晚期调节因子高迁移率族蛋白B1（HMGB1）的分泌，提高脂多糖（LPS）诱导的小鼠脓毒症模型的存活率。LPS诱导的HMGB1分泌可被1,25(OH)D减弱，1,25(OH)D通过阻断巨噬细胞中HMGB1从细胞核向细胞质的转运来实现这一作用。1,25(OH)D可诱导血红素加氧酶-1（HO-1）的表达，这对于阻断HMBG1的核转运及其分泌至关重要。当使用siHO-1或HO-1抑制剂时，1,25(OH)D对抑制HMGB1分泌的作用会受到抑制。鉴于HO-1是核因子E2相关因子2（Nrf2）的下游基因，我们进一步证实，在LPS暴露时，1,25(OH)D可激活Nrf2。总之，我们提供的证据表明，1,25(OH)D通过巨噬细胞中的Nrf2/HO-1途径减弱LPS诱导的HMGB1分泌。
