title: Thymoquinone: An IRAK1 inhibitor with in vivo and in vitro anti-inflammatory activities.
abstract: Thymoquinone (TQ) is a bioactive component of black seed (Nigella sativa) volatile oil and has been shown to have anti-oxidative, anti-inflammatory, and anti-cancer properties. In the present study, we explored the molecular mechanisms that underlie the anti-inflammatory effect of TQ and its target proteins using lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 and human monocyte-like U937 cells, together with LPS/D-galactosamine (GalN)-induced acute hepatitis and HCl/EtOH-induced gastritis mouse models. TQ strongly inhibited the production of nitric oxide (NO) and repressed NO synthase (iNOS), tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, interleukin (IL)-6, and IL-1β expression in LPS-activated RAW264.7 cells. Treatment of LPS/D-GalN-induced hepatitis and EtOH/HCl-induced gastritis mouse models with TQ significantly ameliorated disease symptoms. Using luciferase reporter gene assays, we also showed that the nuclear levels of transcription factors and phosphorylation patterns of signaling proteins, activator protein (AP)-1, and nuclear factor (NF)-κB pathways were all affected by TQ treatment. Finally, we used additional kinase and luciferase validation assays with interleukin-1 receptor-associated kinase 1 (IRAK1) to show that IRAK1 is directly suppressed by TQ treatment. Together, these findings strongly suggest that the anti-inflammatory actions of TQ are caused by suppression of IRAK-linked AP-1/NF-κB pathways.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.|Department of Animal Science, Patuakhali Science and Technology University, Dumki, Patuakhali 8602, Bangladesh.
authors.forename: Muhammad Jahangir
authors.initials: MJ
authors.lastname: Hossen
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Woo Seok
authors.initials: WS
authors.lastname: Yang
authors.affiliation: Laboratory of Bio-informatics, Department of Multimedia Engineering, Dankook University, Cheonan 31116, Republic of Korea.
authors.forename: Daewon
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Physiology, College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea.
authors.forename: Adithan
authors.initials: A
authors.lastname: Aravinthan
authors.affiliation: Department of Physiology, College of Veterinary Medicine, Chonbuk National University, Iksan 54596, Republic of Korea.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea.
authors.forename: Jae Youl
authors.initials: JY
authors.lastname: Cho
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005756:Gastritis / Q000188:drug therapy* / Q000473:pathology / Q000662:veterinary; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D031881:Nigella sativa / Q000737:chemistry* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000067996:RAW 264.7 Cells; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016227:Benzoquinones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C003466:thymoquinone