Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells

Mol Cell Biochem. 2015 Jan;398(1-2):147-56. doi: 10.1007/s11010-014-2214-0. Epub 2014 Sep 19.


Piperine, a kind of natural alkaloid found in peppers, has been reported to exhibit anti-oxidative and anti-tumor activities, both in vitro and in vivo. Interleukin-6 (IL-6) is an important cytokine that activates the signal transduction, promotes tumor cell metastasis, and induces malignancy, including in gastric cancer. However, the effects of piperine on IL-6 expression in gastric cancer cells have not yet been well defined. In this study, we investigated the effects of piperine on the IL-6 expression, and examined the underlying signaling pathways via RT-PCR, promoter studies and Western blotting in human gastric cancer TMK-1 cells. Our results showed that piperine inhibited interleukin-1β (IL-1β)-induced IL-6 expression in a dose-dependent manner. In addition, piperine also inhibited IL-6 promoter activity. Experiments with mitogen-activated protein kinase (MAPK) inhibitors and dominant negative mutant p38 MAPK indicated that p38 MAPK was essential for IL-6 expression in the TMK-1 cells. Additionally, signal transducer and activator of transcription 3 (STAT3) was also involved in the IL-1β-induced IL-6 expression in gastric cancer cells. Piperine inhibited IL-1β-induced p38 MAPK and STAT3 activation and, in turn, blocked the IL-1β-induced IL-6 expression. Furthermore, gastric cancer cells pretreated with IL-1β showed markedly enhanced invasiveness, which was partially abrogated by treatment with IL-6 siRNA, piperine, and inhibitors of p38 MAPK and STAT3. These results suggest that piperine may exert at least part of its anti-cancer effect by controlling IL-6 expression through the suppression of p38 MAPK and STAT3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / pharmacology*
  • Benzodioxoles / pharmacology*
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-1beta / pharmacology*
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism*
  • Mutation
  • Neoplasm Invasiveness
  • Piperidines / pharmacology*
  • Polyunsaturated Alkamides / pharmacology*
  • Pyridines / pharmacology
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / metabolism*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • UDPglucose 4-Epimerase / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • Alkaloids
  • Benzodioxoles
  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-1beta
  • Interleukin-6
  • Piperidines
  • Polyunsaturated Alkamides
  • Pyridines
  • STAT3 Transcription Factor
  • p38 Mitogen-Activated Protein Kinases
  • UDPglucose 4-Epimerase
  • SB 203580
  • piperine