title: Fetal pig beta cells are resistant to the toxic effects of human cytokines.
abstract: BACKGROUND
  The cytokine tumour necrosis factor-alpha (TNF-alpha) is thought to be responsible for primary nonfunction of islets when transplanted. This, and two other cytokines, interleukin-1beta (IL-1beta) and interferon-gamma (IFN-gamma) are also implicated in the autoimmune destruction of beta cells. It is unknown if the fetal pig beta cell, which is being transplanted as a treatment for type 1 diabetes, is affected by these cytokines.
  
  
  METHODS
  We compared the effects of the cytokines on the function and viability of adult and fetal pig beta cells. The cells were cultured for up to 3 days in the presence of 2000 pg/ml of human IL-1beta, 1000 U/ml of TNF-alpha, and 1000 U/ml of IFN-gamma, as well as 1000 U/ml of porcine IFN-gamma. Cumulative insulin levels, insulin content, metabolic activity, and viability of these cells were examined. Additionally, nitric oxide production and the activity of antioxidant enzymes in these cells were also determined.
  
  
  RESULTS
  TNF-alpha and the combination of the three human cytokines caused a transient increase in cumulative insulin levels. TNF-alpha alone enhanced insulin content on day 3. There was no effect of these human cytokines on mitochondrial function and viability. In contrast, porcine IFN-gamma inhibited fetal pig beta cell function and also caused their death. Adult pig islets are sensitive to the toxic effects of human TNF-alpha, IL-1beta, the combination of the three cytokines, and porcine IFN-gamma. The activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase were significantly higher in fetal pig beta cells than in adult islets, implying that this may be the reason for the lack of adverse effects of the cytokines on the fetal beta cell.
  
  
  CONCLUSIONS
  Fetal pig beta cells are resistant to the toxic effect of the human cytokines, TNF-alpha and IL-1beta, in vitro. This resistance suggests that fetal, but not adult beta cells, when transplanted into humans with type 1 diabetes may be protected from primary nonfunction and will be partially protected from autoimmune destruction.
authors.affiliation: Diabetes Transplant Unit, Prince of Wales Hospital and University of New South of Wales, Sydney, New South Wales, Australia.
authors.forename: Lijun
authors.initials: L
authors.lastname: Bai
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Tuch
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hering
authors.forename: Ann M
authors.initials: AM
authors.lastname: Simpson
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000633:toxicity*; D016332:Fetal Tissue Transplantation; D005333:Fetus / Q000187:drug effects*; D006801:Humans; D007328:Insulin / Q000032:analysis; D007371:Interferon-gamma / Q000633:toxicity; D007375:Interleukin-1 / Q000633:toxicity; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D009569:Nitric Oxide / Q000096:biosynthesis; D013482:Superoxide Dismutase / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity
chemical_list: D016207:Cytokines; D007328:Insulin; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D013482:Superoxide Dismutase