Involvement of Toll-like Receptors 2 and 4 in Cellular Activation by High Mobility Group Box 1 Protein*

By Jong Sung Park, D. Svetkauskaite, Q. He, Jae-Yeol Kim, D. Strassheim, A. Ishizaka, E. Abraham. Journal of Biological Chemistry, 2004

1,640 citations recorded by the source corpus.

High mobility group box 1 (HMGB1) protein, originally described as a DNA-binding protein that stabilizes nucleosomes and facilitates transcription, can also be released extracellularly during acute inflammatory responses. Exposure of neutrophils, monocytes, or macrophages to HMGB1 results in increased nuclear translocation of NF-κB and enhanced expression of proinflammatory cytokines. Although the receptor for advanced glycation end products (RAGE) has been shown to interact with HMGB1, other putative HMGB1 receptors are known to exist but have not been characterized. In the present experiments, we explored the role of RAGE, Toll-like receptor (TLR) 2, and TLR 4, as well as associated kinases, in HMGB1-induced cellular activation. Culture of neutrophils or macrophages with HMGB1 produced activation of NF-κB through TLR 4-independent mechanisms. Unlike lipopolysaccharide (LPS), which primarily increased the activity of IKKβ, HMGB1 exposure resulted in activation of both IKKα and IKKβ. Kinases and scaffolding proteins downstream of TLR 2 and TLR 4, but not TLR/interleukin-1 receptor (IL-1R)-independent kinases such as tumor necrosis factor receptor-associated factor 2, were involved in the enhancement of NF-κB-dependent transcription by HMGB1. Transfections with dominant negative constructs demonstrated that TLR 2 and TLR 4 were both involved in HMGB1-induced activation of NF-κB. In contrast, RAGE played only a minor role in macrophage activation by HMGB1. Interactions of HMGB1 with TLR 2 and TLR 4 may provide an explanation for the ability of HMGB1 to generate inflammatory responses that are similar to those initiated by LPS.

Subfields: Clinical Biochemistry, Immunology

View Paper: https://www.semanticscholar.org/paper/ba196c1faa83c0ef4f5894c95ab3f3978144c5c0

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In Clinical Biochemistry

1. Kevin J. Tracey
2. H. Kono
3. K. Rock
4. Michael Lotze
5. M. Bianchi
6. A. Manfredi
7. U. Andersson
8. A. Piccinini

In Immunology

1. Kevin J. Tracey
2. H. Kono
3. K. Rock
4. Michael Lotze
5. M. Bianchi
6. M. Karin
7. Shizuo Akira
8. J. Edwards

Citations in the corpus

• HMGB1: Endogenous Danger Signaling (2008, background): “Furthermore, HMGB1 stimulates the production of reactive oxygen species by neutrophils through a TLR4 dependent activation of NAD(P)H oxidase (72), as well as increases the activation of NF-κB which results in increased production and release of cytokines (50,62).”
• Harmful molecular mechanisms in sepsis (2008, background): “In addition to LPS, various endogenous ligands for TLR4 have been described, including high-mobility group box 1 protein ( HMGB1 ), which is an important mediator during the late phase of sepsis (see later”
• The inflammatory response to cell death. (2008, background): “For example, TLR4 recognizes lipopolysaccarides which are membrane components found in most gram negative bacteria.”
• Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation. (2005, background): “Studies are underway to elucidate the precise contributions of amphoterin–RAGE as well as the interaction of amphoterin with other binding species, such as toll-like receptor-4 and toll-like receptor-2 (TLR-4 and TLR-2) (Park et al., 2004).”
• HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection (2011, background): “This signaling activates IKB kinase (IKK)-β and IKK-α (endotoxin activates only IKK-β) and the nuclear translocation of activated NFκB (24).”
• Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations (2013, neutral): “CPPD crystals were able to induce chondrocyte production of nitric oxide in a TLR2-dependent manner [LiuBryan et  al.”
• High mobility group box 1 protein interacts with multiple Toll-like receptors. (2006, background): “The present experiments, as well as our previous studies (31), indicate that both TLR2 and TLR4 are involved in cellular activation by HMGB1.”
• High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal (2005, result): “Indeed, several functions of HMGB1 are not readily attributable to its interaction with RAGE, and in agreement with the results of Abraham and colleague”
• Exploring the full spectrum of macrophage activation (2008, background): “Macrophages detect the endogenous danger signals that are present in the debris of necrotic cells through Toll-like receptors (TLRs”
• DAMPening Inflammation by Modulating TLR Signalling (2010, background): “Furthermore, whilst the cytokine expression profile induced by HMGB1 versus LPS was similar, a slower induction of TNFα mRNA occurred upon LPS stimulation compared to HMGB1 [20, 104, 105].”