Abstract |
High mobility group box 1 ( HMGB1) is a DNA- binding protein that possesses cytokinelike, proinflammatory properties when released extracellularly in the C23-C45 disulfide form. HMGB1 also plays a key role as a mediator of acute and chronic inflammation in models of sterile injury. Although HMGB1 interacts with multiple pattern recognition receptors ( PRRs), many of its effects in injury models occur through an interaction with toll-like receptor 4 (TLR4). HMGB1 interacts directly with the TLR4/myeloid differentiation protein 2 (MD2) complex, although the nature of this interaction remains unclear. We demonstrate that optimal HMGB1-dependent TLR4 activation in vitro requires the coreceptor CD14. TLR4 and MD2 are recruited into CD14-containing lipid rafts of RAW264.7 macrophages after stimulation with HMGB1, and TLR4 interacts closely with the lipid raft protein GM1. Furthermore, we show that HMGB1 stimulates tumor necrosis factor (TNF)-α release in WT but not in TLR4(-/-), CD14(-/-), TIR domain-containing adapter-inducing interferon-β (TRIF)(-/-) or myeloid differentiation primary response protein 88 (MyD88)(-/-) macrophages. HMGB1 induces the release of monocyte chemotactic protein 1 (MCP-1), interferon gamma-induced protein 10 (IP-10) and macrophage inflammatory protein 1α (MIP-1α) in a TLR4- and CD14-dependent manner. Thus, efficient recognition of HMGB1 by the TLR4/MD2 complex requires CD14.
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Authors | Sodam Kim, Sun Young Kim, John P Pribis, Michael Lotze, Kevin P Mollen, Richard Shapiro, Patricia Loughran, Melanie J Scott, Timothy R Billiar |
Journal | Molecular medicine (Cambridge, Mass.)
(Mol Med)
Vol. 19
Pg. 88-98
(May 20 2013)
ISSN: 1528-3658 [Electronic] England |
PMID | 23508573
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Adaptor Proteins, Vesicular Transport
- Cytokines
- HMGB1 Protein
- Lipopolysaccharide Receptors
- Ly96 protein, mouse
- Lymphocyte Antigen 96
- Myd88 protein, mouse
- Myeloid Differentiation Factor 88
- NF-kappa B
- TICAM-1 protein, mouse
- Tlr4 protein, mouse
- Toll-Like Receptor 4
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Topics |
- Adaptor Proteins, Vesicular Transport
(genetics)
- Animals
- Cell Line
- Cells, Cultured
- Cytokines
(metabolism)
- HEK293 Cells
- HMGB1 Protein
(metabolism)
- Humans
- Lipopolysaccharide Receptors
(genetics, metabolism)
- Lymphocyte Antigen 96
(metabolism)
- Macrophages, Peritoneal
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myeloid Differentiation Factor 88
(genetics)
- NF-kappa B
(metabolism)
- Toll-Like Receptor 4
(genetics, metabolism)
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