title: Induction of HO-1 through p38 MAPK/Nrf2 signaling pathway by ethanol extract of Inula helenium L. reduces inflammation in LPS-activated RAW 264.7 cells and CLP-induced septic mice.
abstract: High mobility group box 1 (HMGB1) plays a crucial mediator in the pathogenesis of many inflammatory diseases. We recently proposed that heme oxygenase-1 (HO-1) negatively regulates HMGB1 in inflammatory conditions. We investigated whether ethanol extract of Inula helenium L. (EIH) activates p38 MAPK/Nrf2/HO-1 pathways in RAW264.7 cells and reduces inflammation in CLP-induced septic mice. EIH induced expression of HO-1 protein in a time- and concentration-dependent manner. EIH significantly diminished HO-1 expression in siNrf2 RNA-transfected cells. As expected, the inhibited expression of iNOS/NO, COX-2/PGE2, HMGB1 release by EIH in LPS-activated RAW264.7 cells was significantly reversed by siHO-1RNA transfection. Furthermore, EIH not only inhibited NF-κB luciferase activity, phosphorylation of IκBα in LPS-activated cells but also significantly suppressed expression of adhesion molecules (ICAM-1 and VCAM-1) in TNF-α activated human umbilical vein endothelial cells. The induction of HO-1 by EIH was inhibited by SB203580 but not by SP600125, PD98059, nor LY294002. Most importantly, administration of EIH significantly reduced not only increase in blood HMGB1, ALT, AST, BUN, creatinine levels but also decrease macrophage infiltrate in the liver of septic mice, which were reversed by ZnPPIX, a HO-1 inhibitor. We concluded that EIH has anti-inflammatory effect via the induction of p38 MAPK-dependent HO-1 signaling pathway.
authors.affiliation: Department of Pharmacology, School of Medicine, Institute of Health Sciences, Gyeongsang National University, Jinju 660-290, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Young Min
authors.initials: YM
authors.lastname: Kim
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Park
authors.forename: Hye Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jae Heun
authors.initials: JH
authors.lastname: Lee
authors.forename: Dong-Ung
authors.initials: DU
authors.lastname: Lee
authors.forename: Ki Churl
authors.initials: KC
authors.lastname: Chang
mesh_terms: D000818:Animals; D002460:Cell Line; D004790:Enzyme Induction; D000431:Ethanol / Q000737:chemistry; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D038143:Inula / Q000737:chemistry*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D018805:Sepsis / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010936:Plant Extracts; D000431:Ethanol; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases