title: Genipin attenuates sepsis by inhibiting Toll-like receptor signaling.
abstract: The pathogenesis of sepsis is characterized by overwhelming inflammatory responses that lead to tissue damage and organ failure. Toll-like receptor (TLR) signaling is crucial for induction of hyperinflammatory responses and tissue injury during sepsis. Genipin, an aglycon of geniposide, has antiinflammatory and antimicrobial activities. The purpose of this study was to test the hypothesis that genipin reduces multiple organ dysfunction and mortality during sepsis through inhibition of TLR signaling. Male ICR were subjected to sepsis by cecal ligation and puncture (CLP) or endotoxemia by lipopolysaccharide (LPS). Various doses of genipin (1, 2.5 and 5 mg/kg) or a vehicle were administered intravenously immediately after CLP or intraperitoneally after LPS treatment. In another set of survival tests, mice were treated with 2.5 mg/kg of genipin 0 and 24 h after CLP. Genipin was found to improve survival and to attenuate multiple organ dysfunction. Genipin attenuated production of proinflammatory cytokines and release of high-mobility group box 1 (HMGB1). Genipin prevented TLR2 and TLR4, myeloid differentiation factor 88 and the Toll/interleukin-1 receptor domain-containing adaptor protein, inducing interferon-β overexpression. Phosphorylation of mitogen-activated protein kinases and interferon regulatory factor 3 and translocation of nuclear factor (NF)-κB were prevented by genipin. Moreover, genipin attenuated increases in serum tumor necrosis factor-α and HMGB1 in LPS-induced endotoxemia. Pam3CSK4- and LPS-mediated production of nitrites and proinflammatory cytokines was suppressed by genipin in RAW264.7 cells. Genipin attenuated mortality and organ injuries during sepsis through interference with TLR signaling. Therefore, genipin might be useful as a potential therapeutic agent for treatment of sepsis.
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Kim
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Yoon
authors.forename: Sun-Mee
authors.initials: SM
authors.lastname: Lee
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D024243:HMGB1 Protein / Q000097:blood; D039823:Iridoids / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D024243:HMGB1 Protein; D039823:Iridoids; D020928:Mitogen-Activated Protein Kinases; D053594:Myeloid Differentiation Factor 88; D009573:Nitrites; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; C007834:genipin