Endogenous HMGB1 is required in endotoxin tolerance
Endogenous HMGB1 is required in endotoxin tolerance
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DOI：
10.1016/j.jss.2013.05.062
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发表时间：
2013-11-01
影响因子：
2.2
通讯作者：
Zhou, Jianda
中科院分区：
文献类型：
--
作者：
Li, Shanshan;Luo, Chengqun;Zhou, Jianda
背景资料：高迁移率族蛋白B1（HMGB 1）是脓毒症和内毒素血症的下游炎症反应调节因子，通过影响细胞低反应性和肿瘤坏死因子α（TNF α）及白细胞介素1（IL 1）的产生来改变内毒素耐受。BALB/c小鼠用0.1 mL低剂量LPS预处理（0.2 mg/kg）或磷酸盐缓冲盐水（PBS）（对照），随后连续三次注射抗HMGB 1、IgY然后在24小时使小鼠经受0.1 mL高剂量LPS（10 mg/kg）或PBS。最终处理后1或3 h采集血清和肝组织样本。在小鼠血清和肝组织中进一步研究了信号机制，用0.1 mL HMGB 1（1 mg/kg），低剂量LPS（0.2 mg/kg），或PBS预处理1 h，然后高剂量LPS处理3 h。结果：参与低剂量LPS预处理的信号机制需要增强内源性HMGB 1的表达和分泌。低剂量LPS预处理后，用抗HMGB 1抗体中和内源性HMGB 1，通过增加血清肿瘤坏死因子α、降低肝脏白细胞介素-1受体相关激酶M表达和部分恢复体内核因子κ B改变内毒素耐受性。结论：低剂量LPS预处理后，RAW264.7细胞内源性HMGB 1表达增加，核因子κ B活性降低，白细胞介素-1受体相关激酶M（IL-1 R-associated kinase M）表达增加，与内毒素耐受有关。这些发现提供了一个更好的机制的理解和开发更安全的临床治疗利用诱导内毒素耐受的基础。(C)2013 Elsevier Inc. All rights reserved.
Background: High-mobility group box 1 protein (HMGB1), a downstream inflammatory response modifier in sepsis and endotoxemia, alters endotoxin tolerance by affecting cellular hyporesponsiveness and tumor necrosis factor alpha and interleukin 1 production.Objective: Endogenous HMGB1 signaling mechanisms during low-dose lipopolysaccharide (LPS)-induced endotoxin tolerance were investigated.Methods: BALB/c mice were preconditioned with either 0.1 mL low-dose LPS (0.2 mg/kg) or phosphate-buffered saline (PBS) (control) followed by treatment with three consecutive injections of anti-HMGB1, IgY (an nonspecific antibody), or PBS, at 2, 12, and 22 h, respectively, Mice were then subjected to 0.1 mL high-dose LPS (10 mg/kg) or PBS at 24 h. Serum and hepatic tissue samples were obtained 1 or 3 h after final treatments. Signaling mechanisms were further investigated in the serum and hepatic tissues of mice preconditioned with 0.1 mL HMGB1 (1 mg/kg), low-dose LPS (0.2 mg/kg), or PBS for 1 h, and then high-dose LPS treatment for 3 h.Results: The signaling mechanisms involved in low-dose LPS preconditioning required enhanced endogenous HMGB1 expression and secretion. Neutralizing endogenous HMGB1 with anti-HMGB1 antibodies following low-dose LPS preconditioning altered endotoxin tolerance by increasing serum tumor necrosis factor alpha, reducing hepatic interleukin-1R-associated kinase M expression, and partially restoring nuclear factor kappa B in vivo. The translocation from nucleus to cytoplasm of endogenous HMGB1 in RAW264.7 cells was also observed during low-dose LPS-induced endotoxin tolerance.Conclusions: Increased interleukin-1R-associated kinase M and decreased nuclear factor kappa B activity in endotoxin tolerance is associated with endogenous HMGB1 expression after low-dose LPS preconditioning. These findings provide a basis for a better mechanistic understanding and the development of safer clinical therapeutics utilizing induced endotoxin tolerance. (C) 2013 Elsevier Inc. All rights reserved.