Abstract
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.