High Mobility Group Box 1 Protein Binding to Lipopolysaccharide Facilitates Transfer of Lipopolysaccharide to CD14 and Enhances Lipopolysaccharide-Mediated TNF-α Production in Human Monocytes
Abstract
LPS-binding protein (LBP) is a central mediator that transfers LPS to CD14 to initiate TLR4-mediated proinflammatory response. However, a possibility of another LPS transfer molecule has been suggested because LBP-deficient mice showed almost normal inflammatory response after LPS injection. In this study, we describe the novel finding that high mobility group box 1 protein (HMGB1) recently identified as a mediator of sepsis has a function of LPS transfer for a proinflammatory response. We used ELISA and surface plasmon resonance to show that HMGB1 binds LPS in a concentration-dependent manner and that the binding is stronger to lipid A moiety than to the polysaccharide moiety of LPS. This binding was inhibited by LBP and polymyxin B. Using native PAGE and fluorescence-based LPS transfer analyses, we show that HMGB1 can catalytically disaggregate and transfer LPS to both soluble CD14 protein and to human PBMCs in a dose-dependent manner. However, this effect was dramatically reduced to the baseline level when HMGB1 was heat inactivated. Furthermore, a mixture of HMGB1 and LPS treatment results in a higher increase in TNF-α production in human PBMCs and peripheral blood monocytes than LPS or HMGB1 treatment alone or their summation. Thus, we propose that HMGB1 plays an important role in Gram-negative sepsis by catalyzing movement of LPS monomers from LPS aggregates to CD14 to initiate a TLR4-mediated proinflammatory response.
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The relevance of observations that purified endogenous molecules induce pro-inflammatory cytokines through TLR2 and/or TLR4 has been questioned because several of these proteins, including HSPs and HMGB1, bind lipopolysaccharide (LPS), making interpretation of pro-inflammatory responses difficult.
“the relevance of these observations has previously been questioned because of the possibility of microbial contamination: several of these proteins, including HSPs and HMGb1, bind lipopolysaccharide (LPS), making the interpretation of pro-inflammatory responses by these molecules difficult28–30.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [30]
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“Furthermore, HMGB1 can also mediate LPS transfer to CD14 to initiate a TLR4-mediated pro-inflammatory response, illustrating the complexity of interactions involving PAMPs, DAMPs and endogenous activators (18).”
Background
- Authors
- Youn, J. H., Oh, Y. J., Kim, E. S., Choi, J. E., & Shin, J.-S.
- Affiliations
- Yonsei University (KR)
- Seoul National University (KR)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-04-01
- Volume
- 180
- Issue
- 7
- Pages
- 5067-5074
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1627944730
- Cited by
- 281
- References
- 55
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 8 · 2023: 7 · 2022: 11 · 2021: 9 · 2020: 15 · 2019: 13 · 2018: 18 · 2017: 10 · 2016: 14 · 2015: 22 · 2014: 20 · 2013: 20 · 2012: 26
- FWCI
- 10.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- HMGB1, lipopolysaccharide, CD14, TLR4, TNF-alpha production, lipid A, sepsis, monocytes, LPS-binding protein, polymyxin B, gram-negative sepsis, pro-inflammatory response
- MeSH terms
- Animals, Catalysis, Cricetulus, Cricetinae, Humans, Leukocytes, Lipopolysaccharides, Micelles, Monocytes, Protein Binding, Solubility, Tumor Necrosis Factor-alpha, CHO Cells, Lipopolysaccharide Receptors, Surface Plasmon Resonance, HMGB1 Protein
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