title: Fructose-1,6-bisphosphate suppresses lipopolysaccharide-induced expression of ICAM-1 through modulation of toll-like receptor-4 signaling in brain endothelial cells.
abstract: Fructose-1,6-bisphosphate (FBP) is a glycolytic intermediate with salutary effects in various brain injury models, but its neuroprotective mechanism is incompletely understood. In this study, we examined the effects of FBP on the expression of adhesion molecules in cerebrovascular endothelial cells and explored the possible mechanisms therein involved. FBP significantly down-regulated lipopolysaccharide (LPS)-induced expression of adhesion molecules and leukocyte adhesion to brain endothelial cells and inhibited NF-κB activity, which is implicated in the expression of adhesion molecules. FBP abrogated ICAM-1 expression and NF-κB activation induced by macrophage-activating lipopeptide 2-kDa (MALP-2) or overexpression of MyD88 or TRAF6. FBP suppressed TRAF6-induced phosphorylation of TAK1, IKKβ and IκBα, but fail to affect NF-κB activity induced by ectopic expression of IKKβ. In addition, LPS-induced IRAK-1 phosphorylation was inhibited by FBP, suggesting the presence of multiple molecular targets of FBP in MyD88-dependent signaling pathway. FBP significantly attenuated ICAM-1 expression and NF-κB activity induced by poly[I:C] or overexpression of TRIF or TBK1. FBP significantly repressed the expression of interferon-β (IFN-β) and the activation of IFN regulatory factor 3 (IRF3) induced by LPS, poly[I:C] or overexpression of TRIF or TBK1, but fail to affect IRF3 activity induced by ectopic expression of constitutively active IRF3. Overall, our results demonstrate that FBP modulates both MyD88- and TRIF-dependent signaling pathways of TLR4 and subsequent inflammatory responses in brain endothelial cells, providing insight into its neuroprotective mechanism in brain injury associated with inflammation.
authors.affiliation: Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Sun Mi
authors.initials: SM
authors.lastname: Seok
authors.affiliation: Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Tae Yeop
authors.initials: TY
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Hye-Si
authors.initials: HS
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon 443-749, Republic of Korea; Department of Physiology, School of Medicine, Ajou University, Suwon 443-749, Republic of Korea.
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Baik
authors.affiliation: Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon 443-749, Republic of Korea; Department of Physiology, School of Medicine, Ajou University, Suwon 443-749, Republic of Korea. Electronic address: shwanlee@ajou.ac.kr.
authors.forename: Soo Hwan
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005635:Fructosediphosphates / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D005635:Fructosediphosphates; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018799:Intercellular Adhesion Molecule-1; C029063:fructose-1,6-diphosphate
keywords: Brain endothelial cell; Fructose-1,6-bisphosphate; Inflammation; Intercellular adhesion molecule-1; Neuroprotection; Toll-like receptor 4