Preconditioning with high mobility group box 1 (HMGB1) induces lipopolysaccharide (LPS) tolerance
Preconditioning with high mobility group box 1 (HMGB1) induces lipopolysaccharide (LPS) tolerance
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DOI：
10.1189/jlb.0108030
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发表时间：
2008-11-01
影响因子：
5.5
通讯作者：
Fink, Mitchell P.
中科院分区：
文献类型：
--
作者：
Aneja, Rajesh K.;Tsung, Allan;Fink, Mitchell P.
当存在于细胞外区室中时调节先天性免疫应答。HMGB 1的受体包括TLR 4、TLR 2和晚期糖基化终产物受体（receptor for advanced glycation end products，简称AGEs）。我们检验了细胞外HMGB 1可以诱导LPS耐受的假设。对IFN-γ分化的人单核细胞样THP-1细胞进行HMGB 1剂量反应实验。在暴露于LPS（1 μ g/ml）前18 h用1 μ g/ml HMGB 1处理可降低TNF释放、NF-κ B核DNA结合活性、磷酸化和I κ B α降解。单独用HMGB 1预处理和在多粘菌素B存在下用HMGB 1预处理降低LPS介导的NF-κ B依赖性荧光素酶报告基因表达。通过显示煮沸的HMGB 1不能诱导耐受，并且针对HMGB 1的抗体阻断LPS耐受的诱导，进一步支持HMGB 1在耐受诱导中的特异性。从C57 B1/6野生型小鼠获得的骨髓来源的巨噬细胞在离体暴露HMGB 1后变得对LPS耐受，但从RAGE缺陷型小鼠获得的巨噬细胞未能产生耐受性并对LPS正常应答。在LPS注射（10 mg/kg）前1 h用HMGB 1（20 μ g）预处理的小鼠与用盐水载体预处理的对照小鼠相比，具有较低的循环TNF。类似地，在用HMGB 1预处理的小鼠中观察到肝NF-κ B的核DNA结合减少。综上所述，这些结果表明，细胞外HMGB 1诱导LPS耐受性，并且这种诱导需要β受体。J. Leukoc. 84：1326-1334; 2008.
modulates the innate immune response when present in the extracellular compartment. Receptors for HMGB1 include TLR4, TLR2, and the receptor for advanced glycation end products ( RAGE). We tested the hypothesis that extracellular HMGB1 can induce LPS tolerance. HMGB1 dose-response experiments were performed on IFN-gamma-differentiated human monocyte-like THP-1 cells. Treatment with 1 mu g/ml HMGB1 18 h before exposure to LPS (1 mu g/ml) decreased TNF release, NF-kappa B nuclear DNA-binding activity, phosphorylation, and degradation of I kappa B alpha. Preconditioning with HMGB1 alone and HMGB1 in the presence of polymyxin B decreased LPS-mediated, NF-kappa B-dependent luciferase reporter gene expression. The specificity of HMGB1 in tolerance induction was supported further by showing that boiled HMGB1 failed to induce tolerance, and antibodies against HMGB1 blocked the induction of LPS tolerance. Bone marrow-derived macrophages obtained from C57Bl/6 wild-type mice became LPS-tolerant following HMGB1 exposure ex vivo, but macrophages derived from RAGE-deficient mice failed to develop tolerance and responded normally to LPS. Mice preconditioned with HMGB1 (20 mu g) 1 h before LPS injection (10 mg/kg) had lower circulating TNF compared with control mice preconditioned with saline vehicle. Similarly, decreased nuclear DNA binding of hepatic NF-kappa B was observed in mice preconditioned with HMGB1. Taken together, these results suggest that extracellular HMGB1 induces LPS tolerance, and the RAGE receptor is required for this induction. J. Leukoc. Biol. 84: 1326-1334; 2008.