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Silymarin Protects Pancreatic ß-Cells against Cytokine-Mediated Toxicity: Implication of c-Jun NH₂-Terminal Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Pathways

Southern California Islet Cell Resources Center (T.M., K.F., I.T., C.V.S., F.K., Y.M.), Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center/Beckman Research Institute, Duarte, California 91010; Department of Surgery (T.M., C.V.S., Y.M.), University of California at Los Angeles, Los Angeles, California 90095; and Department of Gastroenterological Surgery (Y.K.), Graduate School of Medical Sciences, Kobe University, Kobe 650-0017, Japan

Address all correspondence and requests for reprints to: Yoko Mullen, M.D., Ph.D., Southern California Islet Cell Resources Center, Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center/Beckman Research Institute, 1500 East Duarte Road, Duarte, California 91010. E-mail: ymullen{at}coh.org.

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 ß-cells is largely unknown. In this study, the effect of silymarin on IL-1ß and/or interferon (IFN)--induced ß-cell damage was investigated using RINm5F cells and human islets. IL-1ß and/or IFN- 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-1ß and IFN- (IL-1ß+IFN-), 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-1ß+IFN--induced NO production and ß-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 ß-cells and suggest that silymarin may be therapeutically beneficial for type 1 diabetes.