title: Septic shock is associated with receptor for advanced glycation end products ligation of LPS.
abstract: Septic shock is a severe systemic response to bacterial infection. Receptor for advanced glycation end products (RAGE) plays a role in immune reactions to recognize specific molecular patterns as pathogen recognition receptors. However, the interaction between LPS, the bioactive component of bacterial cell walls, and RAGE is unclear. In this study, we found direct LPS binding to RAGE by a surface plasmon resonance assay, a plate competition assay, and flow cytometry. LPS increased TNF-α secretion from peritoneal macrophages and an NF-κB promoter-driven luciferase activity through RAGE. Blood neutrophils and monocytes expressed RAGE, and TLR2 was counterregulated in RAGE(-/-) mice. After LPS injection, RAGE(+/+) mice showed a higher mortality, higher serum levels of IL-6, TNF-α, high mobility group box 1, and endothelin-1, and severe lung and liver pathologies compared with RAGE(-/-) mice without significant differences in plasma LPS level. Administration of soluble RAGE significantly reduced the LPS-induced cytokine release and tissue damage and improved the LPS-induced lethality even in RAGE(-/-) as well as RAGE(+/+) mice. The results thus suggest that RAGE can associate with LPS and that RAGE system can regulate inflammatory responses. Soluble RAGE would be a therapeutic tool for LPS-induced septic shock.
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. yasuyama@med.kanazawa-u.ac.jp
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Ai
authors.initials: A
authors.lastname: Harashima
authors.forename: Hidehito
authors.initials: H
authors.lastname: Saito
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Seiichi
authors.initials: S
authors.lastname: Munesue
authors.forename: So
authors.initials: S
authors.lastname: Motoyoshi
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.forename: Takuo
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Shin
authors.initials: S
authors.lastname: Takasawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimura
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Karasawa
authors.forename: Hideto
authors.initials: H
authors.lastname: Yonekura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive / Q000276:immunology; D045744:Cell Line, Tumor; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood / Q000378:metabolism / Q000502:physiology; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D012772:Shock, Septic / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha