title: Susceptibility of insulin-secreting hepatocytes to the toxicity of pro-inflammatory cytokines.
abstract: 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 beta-cells are killed in type I diabetes is by the release of the cytokines interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) by immune cells. To test the effect of the cytokines on insulin-secreting hepatocytes in vitro we exposed the betacyte, also called the HEP G2ins/g cell which possesses cytokine receptors and can synthesize, store and secrete insulin in a regulated fashion to a glucose stimulus, to the above mentioned cytokines 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 cytokines than the beta-cell line NIT-1. The cytokines had no adverse effect for 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 mM glucose was enhanced 14-fold. Our results indicate that genetically engineered hepatocytes and primary liver cells are more resistant than pancreatic beta-cells to the adverse effects of cytokines offering hope that insulin secreting hepatocytes in vivo made by gene therapy are less likely to be destroyed by cytokines released during autoimmune destruction.
authors.affiliation: Diabetes Transplant Unit, Prince of Wales Hospital and University of New South Wales, Sydney, Australia.
authors.forename: M T
authors.initials: MT
authors.lastname: Tabiin
authors.forename: B E
authors.initials: BE
authors.lastname: Tuch
authors.forename: L
authors.initials: L
authors.lastname: Bai
authors.forename: X G
authors.initials: XG
authors.lastname: Han
authors.forename: A M
authors.initials: AM
authors.lastname: Simpson
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000633:toxicity*; D005260:Female; D005333:Fetus; D005979:Glutathione Peroxidase / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000633:toxicity*; D007328:Insulin / Q000276:immunology / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018121:Receptors, Cytokine / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; D018121:Receptors, Cytokine; D009569:Nitric Oxide; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase