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This version published online on September 30, 2004
Endocrinology, doi:10.1210/en.2004-0850
A more recent version of this article appeared on January 1, 2005
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Submitted on July 6, 2004
Accepted on September 21, 2004

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 (STAT) pathways

Takeru Matsuda, Kevin Ferreri, Ivan Todorov, Yoshikazu Kuroda, Craig V. Smith, Fouad Kandeel, and Yoko Mullen*

Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center/Beckman Research Institute, Duarte, CA USA, Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA & Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kobe University, Kobe, Japan

* To whom correspondence should be addressed. E-mail: ymullen{at}coh.org.

Silymarin is a polyphenolic flavonoid that has a strong antioxidant activity, and exhibits anti-carcinogenic, anti-inflammatory, 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 interleukin (IL)-1{beta} and/or interferon (IFN)-{gamma}-induced {beta}-cell damage was investigated using RINm5F cells and human islets. IL-1{beta} 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-1{beta} and IFN-{gamma} (IL-1{beta}+IFN-{gamma}), for 48 h and 5 days, resulted in an increase of NO production and the impairment of glucose-stimulated insulin secretion, respectively. Silymarin prevented IL-1{beta}+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 (JNK) and Janus kinase/signal transducer and activator of transcription (STAT) pathways. Our data show a direct cytoprotective effect of silymarin in pancreatic {beta}-cells and suggests that silymarin may be therapeutically beneficial for type 1 diabetes.
Key words: Silymarin • JNK • STAT • type1 diabetes






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