title: Piperine inhibits PMA-induced cyclooxygenase-2 expression through downregulating NF-κB, C/EBP and AP-1 signaling pathways in murine macrophages.
abstract: Piperine is a major component of black (Piper nigrum Linn) and long (Piper longum Linn) peppers, and is widely used as a traditional food and medicine. It also exhibits a variety of biological activities, which include antioxidant, anti-tumor and anti-pyretic properties. In the present study, we investigated the inhibitory effects of piperine on phorbol 12-myristate 13-acetate (PMA)-induced cyclooxygenase-2 (COX-2) gene expression and analyzed the molecular mechanism of its activity in murine RAW 264.7 macrophages. Piperine dose-dependently decreased PMA-induced COX-2 expression and PGE(2) production, as well as COX-2 promoter-driven luciferase activity. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, revealed that the nuclear factor-κB (NF-κB), CCAAT/enhancer binding protein (C/EBP) and activator protein-1 (AP-1), were the predominant contributors to the effects of piperine. In addition, piperine inhibited PMA-induced NF-κB, C/EBP and c-Jun nuclear translocation. Furthermore, piperine significantly inhibited PMA-induced activation of the Akt and ERK. These findings demonstrate that piperine effectively attenuates COX-2 production, and provide further insight into the signal transduction pathways involved in the anti-inflammatory effects of piperine.
authors.affiliation: Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hyung Gyun
authors.initials: HG
authors.lastname: Kim
authors.forename: Eun Hee
authors.initials: EH
authors.lastname: Han
authors.forename: Woo-Seok
authors.initials: WS
authors.lastname: Jang
authors.forename: Jae Ho
authors.initials: JH
authors.lastname: Choi
authors.forename: Tilak
authors.initials: T
authors.lastname: Khanal
authors.forename: Bong Hwan
authors.initials: BH
authors.lastname: Park
authors.forename: Thu Phuong
authors.initials: TP
authors.lastname: Tran
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Chung
authors.forename: Hye Gwang
authors.initials: HG
authors.lastname: Jeong
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D052117:Benzodioxoles / Q000494:pharmacology*; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects*; D004789:Enzyme Activation; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D022762:CCAAT-Enhancer-Binding Proteins; D016328:NF-kappa B; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; D011494:Protein Kinases; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; C008922:piperine