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Role of Tumor Necrosis Factor- and Interferon- as Growth Factors to the Human Fetal β-Cell^*

BERNARD E. TUCH, ANN M. SIMPSON and IAIN L. CAMPBELL

Department of Medicine, University of Sydney, New South Wales, and the Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research Parkville, Victoria, Australia

Address all correspondence and requests for reprints to: Bernard E. Tuch, M.D., Ph.D., Department of Endocrinology, Prince of Wales Hospital, Randwick, New South Wales 2031, Australia.

The effects of the cytokines tumor necrosis factor- and interferon- on the adult β-cell have been well described: a reduction of insulin secretion and content and death of the cell. For this reason and because these cytokines may be released from activated lymphocytes and macrophages that infiltrate islets in insulin-dependent diabetes, they have been implicated in the pathophysiology of this form of diabetes. As to whether the human fetal β-cell, which differs from the adult β-cell in not releasing insulin in response to the nutrient glucose and not being adversely affected by the toxin streptozotocin, is similarly affected is unknown. To examine this question we cultured monolayers of a single cell suspension of human fetal pancreas in the presence or absence of 1000 U/mL of these cytokines for 7 days. Chronic insulin release was enhanced for the first 2 days of culture, but unchanged thereafter. Acute insulin release in response to the secretagogue theophylline (10 mM) was enhanced on day 7, but not earlier. There was an increase in the insulin content of the cells by the fourth day, probably due to an increase in the number of β-cells present (45 ± 5% vs. 22 ± 3%). Microscopically, non-β-cells also seemed to increase in number; there was an increase in both DNA and cell number by the seventh day. In contrast to these beneficial effects on the human fetal β-cell, treatment of adult rat insulinoma cells, represented by RIN-m5F cells, resulted in inhibition of insulin secretion during the first day of culture and subsequent death of 86% of the cells by the sixth day of culture. It is hypothesized that the functional immaturity and lack of normal (adult) metabolic activity of the human fetal β-cell somehow confers protection on these cells from the cytotoxic effects of tumor necrosis factor- and interferon-. Indeed, our findings suggest that these cytokines may be trophic for the developing β-cell.

^* This work was supported by research grants from the Juvenile Diabetes Foundation International (JDFI), the Juvenile Diabetes Foundation Australia, and the Hoechst Australia Diabetes Foundation.

t Recipient of a Career Development Award from the JDFI.

Received February 25, 1991.

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