Coptidis rhizoma extract protects against cytokine-induced death of pancreatic β-cells through suppression of NF-κ B activation

Eun-Kyung Kim,Seung-Ryong Yeom,Jin-Woo Park,Kang-San Kim,Raekil Park,Sun-O Ka,Young-Dal Kwon,Mi-Jeong Han,Byung-Hyun Park,Mi-Young Song,Ji-Hyun Lee,Do-Gon Ryu,Kang-Beom Kwon,Na Lv

doi:10.1038/emm.2007.17

Abstract

We demonstrated previously that Coptidis rhizoma extract (CRE) prevented S-nitroso-N-acetylpenicillamine-induced apoptotic cell death via the inhibition of mitochondrial membrane potential disruption and cytochrome c release in RINm5F (RIN) rat insulinoma cells. In this study, the preventive effects of CRE against cytokine-induced beta-cell death was assessed. Cytokines generated by immune cells infiltrating pancreatic islets are crucial mediators of beta-cell destruction in insulin-dependent diabetes mellitus. The treatment of RIN cells with IL-1beta and IFN-gamma resulted in a reduction of cell viability. CRE completely protected IL-1beta and IFN-gamma-mediated cell death in a concentration-dependent manner. Incubation with CRE induced a significant suppression of IL-1beta and IFN-gamma-induced nitric oxide (NO) production, a finding which correlated well with reduced levels of the iNOS mRNA and protein. The molecular mechanism by which CRE inhibited iNOS gene expression appeared to involve the inhibition of NF-kappaB activation. The IL-1beta and IFN-gamma-stimulated RIN cells showed increases in NF-kappaB binding activity and p65 subunit levels in nucleus, and IkappaB alpha degradation in cytosol compared to unstimulated cells. Furthermore, the protective effects of CRE were verified via the observation of reduced NO generation and iNOS expression, and normal insulin-secretion responses to glucose in IL-1beta and IFN-gamma-treated islets.

Highlights

Type 1 diabetes mellitus is an autoimmune disease which induces a selective destruction of the insulinproducing -cells of the Langerhans islets (Nossal et al, 1992)
We recently reported that the pretreatment of RIN cells with Coptidis rhizoma extract (CRE) prevented S-nitroso-N-acetylpenicillamine-induced apoptotic cell death (Kwon et al, 2005)
We have evaluated the preventative effects of CRE on IL-1 and IFN- -induced reductions of viability in -cells

Summary

Introduction

Type 1 diabetes mellitus is an autoimmune disease which induces a selective destruction of the insulinproducing -cells of the Langerhans islets (Nossal et al, 1992). A great deal of evidence supports the crucial role of infiltrating immune cells in and around the pancreatic islets at early stages of pathogenesis (Kanazawa et al, 1984; Jorns et al, 2005). In their activated state, T-lymphocytes and macrophages, which are primary cellular components of islet insulitis, secrete high levels of IL-1 and IFN- , respectively. IL-1 alone, or in combination with TNFor IFN- , induces an excess production of nitric oxide (NO) by the iNOS in the pancreatic islets (Cetkovic-Cvrlje and Eizirik, 1994; Corbett and McDaniel, 1995; Heitmeier et al, 1997; Kwon et al, 2003a). INOS inhibitors, such as Nw-nitro-Larginine methylester (L-NAME) and aminoguanidine, attenuate cytokine-induced -cell dysfunction and islet degeneration (Southern et al, 1990; Welsh et al, 1991; Eizirik et al, 1996)

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Conclusion