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.
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.
Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center/Beckman Research Institute, Duarte, California 91010, USA.
Takeru
T
Matsuda
Kevin
K
Ferreri
Ivan
I
Todorov
Yoshikazu
Y
Kuroda
Craig V
CV
Smith
Fouad
F
Kandeel
Yoko
Y
Mullen
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D019610:Cytoprotection; D004268:DNA-Binding Proteins / Q000378:metabolism; D004338:Drug Combinations; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D012838:Silymarin / Q000494:pharmacology*; D046509:Tissue Culture Techniques; D015534:Trans-Activators / Q000378:metabolism
D000975:Antioxidants; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D007375:Interleukin-1; D008894:Milk Proteins; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D012838:Silymarin; C494088:Stat3 protein, rat; D015534:Trans-Activators; D009569:Nitric Oxide; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases