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

• Published in: Food and chemical toxicology Vol. 55; pp. 386 - 395
• Main Authors: Park, Eun Jung, Kim, Young Min, Park, Sang Won, Kim, Hye Jung, Lee, Jae Heun, Lee, Dong-Ung, Chang, Ki Churl
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.05.2013; Elsevier
• Subjects: alanine transaminase; Animals; anti-inflammatory activity; aspartate transaminase; Biological and medical sciences; blood; Cell Line; creatinine; Diseases; Enzyme Induction; Ethanol; Ethanol - chemistry; Ethyl alcohol; General pharmacology; heme oxygenase (biliverdin-producing); Heme Oxygenase-1 - biosynthesis; HMGB1; HO-1; human umbilical vein endothelial cells; IKappaB kinase; inducible nitric oxide synthase; Inflammation; Inflammation - enzymology; Inflammation - metabolism; Inflammation - prevention & control; Inhibitors; Inula - chemistry; Inula helenium; Lipopolysaccharides - pharmacology; liver; luciferase; macrophages; Medical sciences; Mice; Multiple organ failure; NF-E2-Related Factor 2 - metabolism; nitric oxide; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; pathogenesis; Pathways; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Phosphorylation; Plant Extracts - pharmacology; Sepsis - enzymology; Sepsis - metabolism; Sepsis - physiopathology; Signal Transduction; Toxicology; transcription factor NF-kappa B; transfection; tumor necrosis factor-alpha; Veins; AST; COX-2; EIH; CLP; Multiple organ failure; ALT; HO-1; Inflammation; HMGB1; p38 MAPK; LPS; iNOS; BUN; Mice; Extract; Compositae; Medicinal plant; Sepsis syndrome; Signal transduction; Signaling pathway; Dicotyledones; Angiospermae; Lipopolysaccharide; p38 Mitogen activated protein kinase; Carbohydrate; Enzyme; HMGB1 Protein; Biochemical compound; Transferases; Rodentia; Heme oxygenase (decyclizing); Mitogen-activated protein kinase; Oside; Complex lipid; Infection; Vertebrata; Mammalia; Mouse; Animal; Plant origin; Spermatophyta; Oxidoreductases; Heteroside
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2012.12.027

[Display omitted] ► Heme oxygenase-1 negatively regulated high mobility group box 1 in inflammation. ► Demonstration of a role for p38 MAPK/Nrf2 signal for induction of heme oxygenase-1. ► Inula helenium L. maybe useful for treatment of sepsis.. 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.