Interleukin-6 protects MIN6 beta cells from cytokine-induced apoptosis.
Host nonspecific beta cell injury by cytokines has been implicated in the process of early islet graft dysfunction. Islet transplant destruction by cytokines released from inflammatory cells that infiltrate the graft is thought to be mainly mediated by NF-kappaB-dependent nitric oxide (NO) production by the islet. In this study, we aimed to evaluate the role of IL-6 in making a beta cell resistant to cytokine-induced apoptosis by decreasing the NF-kappaB-dependent NO production and compared the result with that of the expression of a dominant negative inhibitor of NF-kappaB (DN NF-kappaB). Incubation of MIN6 cells with IL-1beta, IFN-gamma, and TNF-alpha (cytomix) increased production of nitrites, with increased expression of iNOS mRNA. When treated with cytomix, the DN NF-kappaB-transfected mutant demonstrated significantly less nitrite production and apoptosis than parent MIN6. NO production was effectively blocked by IL-6 as well as by N-monomethyl-l-arginine (l-NMMA). Inhibition of the NO production led to decreased rate of apoptosis accompanied by downregulation of the proapoptotic molecule Bax and increased expression of the antiapoptotic molecule Bcl-2 and Bcl-x(L). These data indicate that cytokine-induced cell death in the MIN6 beta cell line involves mechanisms that are, in part, NF-kappaB- and NO-dependent. Inhibition of the NO production by the incubation of the MIN6 cells by the pretreatment of IL-6 or l-NMMA is cytoprotective and can be used as a substitute for the expression of DN NF-kappaB.
Park
Hyewon
H
Division of Endocrinology and Metabolism, Department of Internal Medicine and Microbiology, Hanyang and Seoul National University, Seoul, Korea.
Ahn
Yuhern
Y
Park
Chung-Kyu
CK
Chung
Hee-Yong
HY
Park
Yongsoo
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D015850:Interleukin-6 / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000235:genetics
D016207:Cytokines; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse