Abstract
Abstract Activation of innate immunity via TLRs plays a pivotal role in host defense against pathogens through the recognition of PAMPs. However, since uncontrolled immune response leads to various kinds of autoimmune and inflammatory diseases, TLR signaling should be tightly regulated. Recent studies have shown that HMGB1 could be critical for the control of TLR signaling. In this study, we demonstrated that HMGB1 mediated negative regulating signals of TLR activation. Our data indicated that HMGB1 induced NF-κB activation via non-canonical pathway by processing of p100 to p52 and translocation of p52 into the nucleus. Also, HMGB1 induced expression of TRIM30α which is a regulator of TLR signaling. Preconditioned HMGB1 attenuated TLR activation by LPS in murine, human macrophage cell lines and mouse BMDM. Treatment of HMGB1 followed by LPS stimulation decreased TNF-α and IL-6 level in mouse BMDM when compared with LPS stimulation alone. Furthermore, HMGB1 pretreatment in the presence of polymyxin B, an endotoxin inactivator, induced HMGB1-mediated tolerance. Pretreatment of HMGB1 promoted rapid termination of signaling in macrophage cells through transcription factor NF-κB by augmenting negative regulators of TLRs such as TRIM30α and SHIP-1. Knockdown experiments using TRIM30α-specific small interfering RNA impaired the HMGB1-mediated TLR tolerance. Collectively, our results demonstrate that HMGB1 mediated the mechanism for prevention of excessive TLR-mediated inflammation.
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