Susceptibility of insulin-secreting hepatocytes to the toxicity of pro-inflammatory cytokines

The liver has been suggested as a-suitable target organ for reversing type I diabetes by gene therapy. Whilst gene delivery systems to the hepatocyte have yet to be optimized in vivo, whether insulin-secreting hepatocytes are resistant to the autoimmune process that kills pancreatic beta -cells has never been addressed. One of the mechanisms by which P-cells are killed in type I diabetes is by the release of the cytokines interleukin-1 beta (IL-1 beta), tumour necrosis factor-a (TNF-a) and interferon-gamma (IFN-y) by im mune cells. To test the effect of the cytokines on insulin-secreting hepato cytes in vitro we exposed the betacyte, also called the HEP G2ins/g cell wh ich possesses cytokine receptors and can synthesize, store and secrete insu lin in a regulated fashion to a glucose stimulus, to the above mentioned cy tokines for 14 days. Viability of the HEP G2ins/g cells was similar to that of other liver cell lines/primary cells which were more resistant to the c ytokines than the P-cell line NIT-1. The cytokines. had no adverse effect f or the first six days on insulin secretion, content and mRNA levels of the HEP G2ins/g cells and insulin secretion in response to 1-h exposure to 20 m M glucose was enhanced 14-fold. Our results indicate that genetically engin eered hepatocytes and primary liver cells are more resistant than pancreati c P-cells to the adverse effects of cytokines offering hope that insulin se creting hepatocytes in vivo made by gene therapy are less likely to be dest royed by cytokines released during autoimmune destruction. (C) 2001 Academi c Press.