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Cytotoxic Effects of Cytokines on Human Pancreatic Islet Cells in Monolayer Culture^*

Departments of Medicine (A.R., W.S.) and Surgery (R.V.R., G.L.W.) and the Muttart Diabetes Research and Training Centre, University of Alberta Edmonton, Alberta, Canada

Address all correspondence and requests for reprints to: Alexander Rabinovitch, M.D., 430 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.

Interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon- (IFN) inhibit insulin release and may be cytotoxic to isolated rodent pancreatic islets. In this study we examined the effects of IL-1, TNF, and IFN on the viability and hormone secretion of islets isolated from adult human pancreas and maintained in monolayer culture. IL-1 and TNF were cytotoxic to the islet cells (20-30% cell lysis) in a ⁵¹Cr release cytotoxicity assay, and IFN had only small effects (<10% lysis). Combination of maximally cytotoxic concentrations of IL-1 (10 U/mL) and TNF (10³ U/mL) produced an additive cytotoxic effect. IFN (10³ U/mL) acted synergistically with IL-1 and TNF, and the three cytokines added together produced maximal islet cell lysis (46.4 ± 4.3%). Assay of insulin and glucagon in the islet monolayers revealed that IL-1, TNF, and IFN inhibited both B- and A-cell secretory functions; however, only IL-1 and TNF produced permanent decreases in insulin and glucagon contents in the islet cultures. These findings indicate that IL-1 and TNF, as single agents, are cytotoxic to human islet cells, and that this cytotoxicity can be amplified by combining the cytokines and/or adding IFN. However, the lack of specificity for B-cells in vitro suggests that additional factors might be operative in vivo for the cytokine products of macrophages and lymphocytes infiltrating islets to produce the B-cell-specific damage characteristic of type 1 diabetes.

^* This work was supported by the Alberta Heritage Foundation for Medical Research and the Muttart Diabetes Research and Training Centre.

Received August 3, 1989.

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