Resveratrol enhances perforin expression and NK cell cytotoxicity through NKG2D-dependent pathways

J Cell Physiol. 2010 May;223(2):343-51. doi: 10.1002/jcp.22043.

Abstract

In a previous report, we showed that the in vivo cytotoxic activity of the natural killer (NK) cells isolated from resveratrol-pretreated rats is significantly enhanced compared with that of the non-pretreated rats; however, the underlying mechanism remains unclear. In the present study, we use cultured NK92 cell line to examine the possible signaling pathways underlying the resveratrol-induced activation. Using cultured K562, HepG2, and A549 cells as targets, we show that resveratrol pretreatment increases NK cell cytotoxicity in a dose-dependent manner. The enhanced cytotoxic effect is accompanied by increases in JNK and ERK-1/2 MAP kinase activity and perforin expression. Moreover, the expression of NKG2D, an upstream signaling molecule of the MAP kinases pathway, is also enhanced. Resveratrol-enhanced perforin expression and cytotoxic activity are effectively inhibited by pretreatment with the inhibitors of JNK (SP600125), ERK-1/2 (PD98059), or by siRNAs against JNK-1 and ERK-2. However, the inhibitors or siRNA to p38 exhibits no effect. Since IL-2 has been shown to induce NKG2D expression and perforin release, we therefore, examined whether IL-2 and resveratrol act in parallel. We show that IL-2 also stimulates perforin expression, however, when treated together with resveratrol, they exhibit no additive effect. The results suggest that in NK92 cells, resveratrol may act via a similar or overlapping pathway as that of IL-2, to enhance perforin expression and cytotoxic activity. Data presented strongly indicate that resveratrol act via NKG2D-dependent JNK and ERK-1/2 pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antioxidants / pharmacology
  • Cell Line
  • Cytotoxicity, Immunologic / drug effects
  • Cytotoxicity, Immunologic / physiology
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Immunity, Innate / drug effects*
  • Immunity, Innate / physiology
  • Interleukin-2 / pharmacology
  • JNK Mitogen-Activated Protein Kinases / drug effects
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / metabolism
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / physiology
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • NK Cell Lectin-Like Receptor Subfamily K / drug effects*
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Perforin / agonists*
  • Perforin / metabolism
  • RNA Interference / drug effects
  • RNA Interference / physiology
  • Resveratrol
  • Stilbenes / pharmacology*
  • Up-Regulation / drug effects
  • Up-Regulation / physiology

Substances

  • Antioxidants
  • Enzyme Inhibitors
  • Interleukin-2
  • KLRK1 protein, human
  • NK Cell Lectin-Like Receptor Subfamily K
  • Stilbenes
  • Perforin
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Resveratrol