title: AP-1 pathway-targeted inhibition of inflammatory responses in LPS-treated macrophages and EtOH/HCl-treated stomach by Archidendron clypearia methanol extract.
abstract: BACKGROUND
  Archidendron clypearia Jack. (Fabaceae) is a representative ethnomedicinal herbal plant prescribed for various inflammatory diseases such as pharyngolaryngitis and tonsillitis. However, the pharmacology behind this plant's anti-inflammatory properties has not been fully understood. Therefore, in this study, the anti-inflammatory mechanism of a 95% methanol extract (Ac-ME) was explored.
  
  
  METHODS
  The anti-inflammatory mechanism of Ac-ME on the AP-1 activation pathway, which plays a critical role in the production of prostaglandin (PG)E2 in RAW264.7 cells and peritoneal macrophages and in induction of acute gastritis caused by HCl/EtOH, was investigated using immunoblotting, immunoprecipitation analyses, and reporter gene activity assays. In particular, enzyme assays and HPLC analysis were employed to identify direct target enzymes of Ac-ME and to detect active chemical components from the plant extract.
  
  
  RESULTS
  Ac-ME clearly reduced the nuclear levels of total and phospho-forms of c-Jun, FRA-1, and ATF-2. Consequently, this extract suppressed both the production of PGE2 in lipopolysaccharide (LPS)-activated RAW264.7 and peritoneal macrophage cells and PGE2-dependent induction of gastritis lesion in stomach under EtOH/HCl exposure. Analysis of AP-1 upstream signalling revealed that the AP-1 activation pathway consisting of IRAK1, TRAF6, TAK1, MKK3/6, and p38 was predominantly inhibited by Ac-ME. Similarly, this extract directly blocked the enzyme activity of IRAK1, indicating that this enzyme is an inhibitory target of Ac-ME and is involved in the suppression of the AP-1 pathway. HPLC analysis showed that quercetin, which inhibits PGE2 production, is an active component in Ac-ME.
  
  
  CONCLUSIONS
  Ac-ME is an ethnomedicinal remedy with an IRAK1/p38/AP-1-targeted inhibitory property. Since AP-1 is a major inflammation-inducing transcription factor, the therapeutic potential of Ac-ME in other AP-1-mediated inflammatory symptoms will be further tested.
authors: Department of Genetic Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors: Woo Seok
authors: WS
authors: Yang
authors: Deok
authors: D
authors: Jeong
authors: Gyeongsug
authors: G
authors: Nam
authors: Young-Su
authors: YS
authors: Yi
authors: Deok Hyo
authors: DH
authors: Yoon
authors: Tae Woong
authors: TW
authors: Kim
authors: Yung Chul
authors: YC
authors: Park
authors: Hyunsik
authors: H
authors: Hwang
authors: Man Hee
authors: MH
authors: Rhee
authors: Sungyoul
authors: S
authors: Hong
authors: Jae Youl
authors: JY
authors: Cho
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D000431:Ethanol; D007887:Fabaceae; D005756:Gastritis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D006851:Hydrochloric Acid; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D000432:Methanol / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology / Q000627:therapeutic use*; D018515:Plant Leaves; D018547:Plant Stems; D012997:Solvents / Q000737:chemistry; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D010936:Plant Extracts; D012997:Solvents; D018808:Transcription Factor AP-1; D000431:Ethanol; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D015232:Dinoprostone; D006851:Hydrochloric Acid; D000432:Methanol