Silymarin Protects Pancreatic Beta-Cells Against Cytokine-Mediated Toxicity: Implication of c-Jun NH2-terminal Kinase and Janus kinase/signal Transducer and Activator of Transcription Pathways

Endocrinology. 2005 Jan;146(1):175-85. doi: 10.1210/en.2004-0850. Epub 2004 Sep 30.

Abstract

Silymarin is a polyphenolic flavonoid that has a strong antioxidant activity and exhibits anticarcinogenic, antiinflammatory, and cytoprotective effects. Although its hepatoprotective effect has been well documented, the effect of silymarin on pancreatic beta-cells is largely unknown. In this study, the effect of silymarin on IL-1beta and/or interferon (IFN)-gamma-induced beta-cell damage was investigated using RINm5F cells and human islets. IL-1beta and/or IFN-gamma induced cell death in a time-dependent manner in RINm5F cells. The time-dependent increase in cytokine-induced cell death appeared to correlate with the time-dependent nitric oxide (NO) production. Silymarin dose-dependently inhibited both cytokine-induced NO production and cell death in RINm5F cells. Treatment of human islets with a combination of IL-1beta and IFN-gamma (IL-1beta+IFN-gamma), for 48 h and 5 d, resulted in an increase of NO production and the impairment of glucose-stimulated insulin secretion, respectively. Silymarin prevented IL-1beta+IFN-gamma-induced NO production and beta-cell dysfunction in human islets. These cytoprotective effects of silymarin appeared to be mediated through the suppression of c-Jun NH2-terminal kinase and Janus kinase/signal transducer and activator of transcription pathways. Our data show a direct cytoprotective effect of silymarin in pancreatic beta-cells and suggest that silymarin may be therapeutically beneficial for type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Biological Transport / drug effects
  • Cell Death / drug effects
  • Cell Line
  • Cell Nucleus / metabolism
  • Cytoprotection*
  • DNA-Binding Proteins / metabolism
  • Drug Combinations
  • Enzyme Activation / drug effects
  • Humans
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / pharmacology*
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / pharmacology*
  • Islets of Langerhans / drug effects*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Milk Proteins / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-kappa B / physiology
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase Type II
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Signal Transduction / physiology
  • Silymarin / pharmacology*
  • Tissue Culture Techniques
  • Trans-Activators / metabolism

Substances

  • Antioxidants
  • DNA-Binding Proteins
  • Drug Combinations
  • Interleukin-1
  • Milk Proteins
  • NF-kappa B
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • STAT5 Transcription Factor
  • Silymarin
  • Stat3 protein, rat
  • Trans-Activators
  • Nitric Oxide
  • Interferon-gamma
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, rat
  • Protein-Tyrosine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases