title: Inhibition of IRAK-4 activity for rescuing endotoxin LPS-induced septic mortality in mice by lonicerae flos extract.
abstract: Lonicerae flos extract (HS-23) is a clinical candidate currently undergoing Phase I trial in lipopolysaccharide (LPS)-injected healthy human volunteers, but its molecular basis remains to be defined. Here, we investigated protective effects of HS-23 or its major constituents on Escherichia coli LPS-induced septic mortality in mice. Intravenous treatment with HS-23 rescued LPS-intoxicated C57BL/6J mice under septic conditions, and decreased the levels of cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and high-mobility group box-1 (HMGB-1) in the blood. Chlorogenic acid (CGA) and its isomers were assigned as major constituents of HS-23 in the protection against endotoxemia. As a molecular mechanism, HS-23 or CGA isomers inhibited endotoxin LPS-induced autophosphorylation of the IL-1 receptor-associated kinase 4 (IRAK-4) in mouse peritoneal macrophages as well as the kinase activity of IRAK-4 in cell-free reactions. HS-23 consequently suppressed downstream pathways critical for LPS-induced activation of nuclear factor (NF)-κB or activating protein 1 (AP-1) in the peritoneal macrophages. HS-23 also inhibited various toll-like receptor agonists-induced nitric oxide (NO) production, and down-regulated LPS-induced expression of NF-κB/AP-1-target inflammatory genes in the cells. Taken together, HS-23 or CGA isomers exhibited anti-inflammatory therapy against LPS-induced septic mortality in mice, at least in part, mediated through the inhibition of IRAK-4.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea.
authors.forename: Sun Hong
authors.initials: SH
authors.lastname: Park
authors.forename: Eunmiri
authors.initials: E
authors.lastname: Roh
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Kim
authors.forename: Seung-Il
authors.initials: SI
authors.lastname: Baek
authors.forename: Nam Song
authors.initials: NS
authors.lastname: Choi
authors.forename: Narae
authors.initials: N
authors.lastname: Kim
authors.forename: Bang Yeon
authors.initials: BY
authors.lastname: Hwang
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Han
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002726:Chlorogenic Acid / Q000032:analysis / Q000737:chemistry / Q000627:therapeutic use*; D004731:Endotoxins; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides; D031239:Lonicera / Q000737:chemistry*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010936:Plant Extracts / Q000737:chemistry / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000401:mortality; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010936:Plant Extracts; D018808:Transcription Factor AP-1; D002726:Chlorogenic Acid; C588038:lonicerae flos; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse
keywords: AP-1; Anti-inflammatory therapy; CGA; Chlorogenic acid isomers; Endotoxin LPS; HS-23; IL-1 receptor-associated kinase 4; IRAK-4; Lonicerae flos extract; MyD88; NF-κB; Septic mortality; TBK-1; TLR; TNF receptor-associated factor (TRAF) family member-associated NF-κB activator (TANK)-binding kinase 1; TRIF; activating protein 1; chlorogenic acid; lonicerae flos extract; myeloid differentiation factor 88; nuclear factor-κB; toll-like receptor; toll/IL-1 receptor (TIR)-containing adaptor inducing IFN-β