HMGB1 Binds to Lipoteichoic Acid and Enhances TNF-α and IL-6 Production through HMGB1-Mediated Transfer of Lipoteichoic Acid to CD14 and TLR2.

Abstract

Lipoteichoic acid (LTA) is a component of the cell wall of Gram-positive bacteria and induces a toll-like receptor 2 (TLR2)-mediated inflammatory response upon initial binding to lipopolysaccharide-binding protein (LBP) and subsequent transfer to CD14. In this study, we identified a novel role for the nuclear protein high-mobility group box 1 (HMGB1) in LTA-mediated inflammation. Results of ELISA, surface plasmon resonance and native PAGE electrophoretic mobility shift analyses indicated that HMGB1 binds to LTA in a concentration-dependent manner and that this binding is inhibited by LBP. Native PAGE, fluorescence-based transfer and confocal imaging analyses indicated that HMGB1 catalytically disaggregates LTA and transfers LTA to CD14. NF-κB p65 nuclear transmigration, degradation of IκBα and reporter assay results demonstrated that NF-κB activity in HEK293-hTLR2/6 cells is significantly upregulated by a mixture of LTA and soluble CD14 in the presence of HMGB1. Furthermore, the production of TNF-α and IL-6 in J774A.1 and RAW264.7 cells increased significantly following treatment with a mixture of LTA and HMGB1 compared with treatment with LTA or HMGB1 alone. Thus, we propose that HMGB1 plays an important role in LTA-mediated inflammation by binding to and transferring LTA to CD14, which is subsequently transferred to TLR2 to induce an inflammatory response.

• Authors: Man Sup Kwak, Mihwa Lim, Yong Joon Lee, Hyun Sook Lee, Young Hun Kim, Ju Ho Youn, Ji Eun Choi, Jeon-Soo Shin
• Journal: Journal of innate immunity (J Innate Immun) Vol. 7 Issue 4 Pg. 405-16 ( 2015) ISSN: 1662-8128 [Electronic] Switzerland
• PMID: 25660311 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HMGB1 Protein
• HMGB1 protein, human
• IL6 protein, human
• Interleukin-6
• Lipopolysaccharide Receptors
• Lipopolysaccharides
• TLR2 protein, human
• Teichoic Acids
• Toll-Like Receptor 2
• Tumor Necrosis Factor-alpha
• lipoteichoic acid

Topics

• HEK293 Cells
• HMGB1 Protein (genetics, immunology, metabolism)
• Humans
• Interleukin-6 (genetics, immunology, metabolism)
• Lipopolysaccharide Receptors (genetics, immunology)
• Lipopolysaccharides (genetics, immunology, metabolism)
• Protein Binding (genetics, immunology)
• Teichoic Acids (genetics, immunology, metabolism)
• Toll-Like Receptor 2 (genetics, immunology)
• Tumor Necrosis Factor-alpha (genetics, immunology, metabolism)