Gene interactions and pathways from curated databases and text-mining
Shock 2006, PMID: 16878026

HMGB1 signals through toll-like receptor (TLR) 4 and TLR2.

Yu, Man; Wang, Haichao; Ding, Aihao; Golenbock, Douglas T; Latz, Eicke; Czura, Christopher J; Fenton, Matthew J; Tracey, Kevin J; Yang, Huan

In response to bacterial endotoxin (e.g., LPS) or endogenous proinflammatory cytokines (e.g., TNF and IL-1beta), innate immune cells release HMGB1, a late cytokine mediator of lethal endotoxemia and sepsis. The delayed kinetics of HMGB1 release makes it an attractive therapeutic target with a wider window of opportunity for the treatment of lethal systemic inflammation. However, the receptor(s) responsible for HMGB1-mediated production of proinflammatory cytokines has not been well characterized. Here we demonstrate that in human whole blood, neutralizing antibodies against Toll-like receptor 4 (TLR4, but not TLR2 or receptor for advanced glycation end product) dose-dependently attenuate HMGB1-induced IL-8 release. Similarly, in primary human macrophages, HMGB1-induced TNF release is dose-dependently inhibited by anti-TLR4 antibodies. In primary macrophages from knockout mice, HMGB1 activates significantly less TNF release in cells obtained from MyD88 and TLR4 knockout mice as compared with cells from TLR2 knockout and wild-type controls. However, in human embryonic kidney 293 cells transfected with TLR2 or TLR4, HMGB1 effectively induces IL-8 release only from TLR2 overexpressing cells. Consistently, anti-TLR2 antibodies dose-dependently attenuate HMGB1-induced IL-8 release in human embryonic kidney/TLR2-expressing cells and markedly reduce HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells. Taken together, our data suggest that there is a differential usage of TLR2 and TLR4 in HMGB1 signaling in primary cells and in established cell lines, adding complexity to studies of HMGB1 signaling which was not previously expected.

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Text Mining Data

IL-8 → HMGB1: " Here we demonstrate that in human whole blood, neutralizing antibodies against Toll-like receptor 4 ( TLR4, but not TLR2 or receptor for advanced glycation end product ) dose-dependently attenuate HMGB1 induced IL-8 release "

TNF → HMGB1: " Similarly, in primary human macrophages, HMGB1 induced TNF release is dose-dependently inhibited by anti-TLR4 antibodies "

TNF → HMGB1: " Similarly, in primary human macrophages, HMGB1 induced TNF release is dose-dependently inhibited by anti-TLR4 antibodies "

TNF → HMGB1: " In primary macrophages from knockout mice, HMGB1 activates significantly less TNF release in cells obtained from MyD88 and TLR4 knockout mice as compared with cells from TLR2 knockout and wild-type controls "

TNF → HMGB1: " In primary macrophages from knockout mice, HMGB1 activates significantly less TNF release in cells obtained from MyD88 and TLR4 knockout mice as compared with cells from TLR2 knockout and wild-type controls "

HMGB1 → IL-8: " However, in human embryonic kidney 293 cells transfected with TLR2 or TLR4, HMGB1 effectively induces IL-8 release only from TLR2 overexpressing cells "

HMGB1 → IL-8: " However, in human embryonic kidney 293 cells transfected with TLR2 or TLR4, HMGB1 effectively induces IL-8 release only from TLR2 overexpressing cells "

IL-8 → HMGB1: " Consistently, anti-TLR2 antibodies dose-dependently attenuate HMGB1 induced IL-8 release in human embryonic kidney/TLR2 expressing cells and markedly reduce HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells "

Manually curated Databases

  • NCI Pathway Database Endogenous TLR signaling: TLR1 (TLR1) → HMGB1 (HMGB1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Endogenous TLR signaling: TLR1 (TLR1) → HMGB1/TLR2/TLR1 complex (TLR2-TLR1-HMGB1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Endogenous TLR signaling: TLR1 (TLR1) → TLR2 (TLR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Endogenous TLR signaling: HMGB1 (HMGB1) → HMGB1/TLR2/TLR1 complex (TLR2-TLR1-HMGB1) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Endogenous TLR signaling: HMGB1 (HMGB1) → TLR2 (TLR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Endogenous TLR signaling: HMGB1/TLR2/TLR1 complex (TLR2-TLR1-HMGB1) → TLR2 (TLR2) (modification, collaborate)
    Evidence: mutant phenotype, assay, physical interaction
  • NCI Pathway Database Endogenous TLR signaling: HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP complex (TLR4-LY96-HMGB1-MYD88-TIRAP) → HMGB1/TLR4/MD2 (dimer) complex (TLR4-LY96-HMGB1) (modification, collaborate)
    Evidence: mutant phenotype
  • NCI Pathway Database Endogenous TLR signaling: HMGB1/TLR4/MD2 (dimer)/MYD88/TIRAP complex (TLR4-LY96-HMGB1-MYD88-TIRAP) → MYD88/TIRAP complex (MYD88-TIRAP) (modification, collaborate)
    Evidence: mutant phenotype
  • NCI Pathway Database Endogenous TLR signaling: HMGB1/TLR4/MD2 (dimer) complex (TLR4-LY96-HMGB1) → MYD88/TIRAP complex (MYD88-TIRAP) (modification, collaborate)
    Evidence: mutant phenotype
  • NCI Pathway Database Endogenous TLR signaling: HMGB1/TLR2/TLR1 complex (TLR2-TLR1-HMGB1) → MYD88/TIRAP complex (MYD88-TIRAP) (modification, collaborate)
    Evidence: mutant phenotype
  • NCI Pathway Database Endogenous TLR signaling: HMGB1/TLR2/TLR1 complex (TLR2-TLR1-HMGB1) → HMGB1/TLR2/TLR1/MYD88/TIRAP complex (TLR2-TLR1-HMGB1-MYD88-TIRAP) (modification, collaborate)
    Evidence: mutant phenotype
  • NCI Pathway Database Endogenous TLR signaling: MYD88/TIRAP complex (MYD88-TIRAP) → HMGB1/TLR2/TLR1/MYD88/TIRAP complex (TLR2-TLR1-HMGB1-MYD88-TIRAP) (modification, collaborate)
    Evidence: mutant phenotype
In total, 24 gene pairs are associated to this article in curated databases