Piperine inhibits PMA-induced cyclooxygenase-2 expression through downregulating NF-κB, C/EBP and AP-1 signaling pathways in murine macrophages

Food Chem Toxicol. 2012 Jul;50(7):2342-8. doi: 10.1016/j.fct.2012.04.024. Epub 2012 Apr 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Animals
  • Benzodioxoles / pharmacology*
  • Blotting, Western
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cell Line
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Dinoprostone / biosynthesis
  • Down-Regulation / drug effects*
  • Enzyme Activation
  • Humans
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • NF-kappa B / metabolism*
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / pharmacology*
  • Protein Kinases / metabolism
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Tetradecanoylphorbol Acetate / antagonists & inhibitors*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor AP-1 / metabolism*


  • Alkaloids
  • Benzodioxoles
  • CCAAT-Enhancer-Binding Proteins
  • NF-kappa B
  • Piperidines
  • Polyunsaturated Alkamides
  • Transcription Factor AP-1
  • Cyclooxygenase 2
  • Protein Kinases
  • Dinoprostone
  • Tetradecanoylphorbol Acetate
  • piperine