Children's Hospital of Alabama, Birmingham, USA.
J Immunother. 2010 Sep;33(7):663-71. doi: 10.1097/CJI.0b013e3181dcd111.
High mobility group box chromosomal protein 1 (HMGB1) is a DNA-binding protein that exhibits proinflammatory properties when present in the extracellular compartment. Putative receptors for HMGB1 include Toll-like receptor (TLR)4, TLR2, and the receptor for advanced glycation end products (RAGE). We tested the hypothesis that extracellular HMGB1 can induce tolerance to the bacterial product, lipoteichoic acid (LTA). Pretreatment of human monocyte-like THP-1 cells with 1 μg/mL HMGB1 18 hours before exposure to LTA (10 μg/mL) decreased secretion of tumor necrosis factor, nuclear factor-κB DNA-binding, and degradation of IκBα. Denaturation of HMGB1 with boiling water or coincubation with anti-HMGB1 antibody abrogated the induction of tolerance to LTA. In contrast, coincubation with polymyxin B failed to diminish HMGB1-induced tolerance to LTA. These findings support the view that the induction of LTA tolerance by HMGB1 was not due to lipopolysaccharide contamination. Bone marrow-derived macrophages obtained from C57Bl/6 wild-type and RAGE-deficient mice became LTA-tolerant after HMGB1 exposure ex vivo. We were unable to demonstrate LTA tolerance in TLR2 and TLR4-deficient macrophages, as they are hyporesponsive to LTA. These findings suggest that extracellular HMGB1 induces LTA tolerance, and RAGE receptor is not required for this induction.
高迁移率族蛋白 B1（HMGB1）是一种 DNA 结合蛋白，当其存在于细胞外区室时具有促炎特性。HMGB1 的假定受体包括 Toll 样受体（TLR）4、TLR2 和晚期糖基化终产物受体（RAGE）。我们检验了这样一个假设，即细胞外 HMGB1 可以诱导对细菌产物脂磷壁酸（LTA）的耐受。在暴露于 LTA（10μg/ml）之前 18 小时，用 1μg/ml HMGB1 预处理人单核细胞样 THP-1 细胞，可减少肿瘤坏死因子的分泌、核因子-κB DNA 结合和 IκBα 的降解。用沸水使 HMGB1 变性或与抗 HMGB1 抗体共孵育，可消除对 LTA 的诱导耐受。相比之下，与多粘菌素 B 共孵育并不能减少 HMGB1 诱导的对 LTA 的耐受。这些发现支持了这样一种观点，即 HMGB1 诱导 LTA 耐受不是由于脂多糖污染所致。从 C57Bl/6 野生型和 RAGE 缺陷型小鼠获得的骨髓来源的巨噬细胞在暴露于 HMGB1 后在体外成为 LTA 耐受。我们未能在 TLR2 和 TLR4 缺陷型巨噬细胞中证明 LTA 耐受，因为它们对 LTA 的反应性降低。这些发现表明，细胞外 HMGB1 诱导 LTA 耐受，而 RAGE 受体不是这种诱导所必需的。
