EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA, TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA ON PANCREATIC-ISLET BETA-CELL RESPONSIVENESS TO TRANSFORMING GROWTH-FACTOR-ALPHA

The insulin-producing pancreatic islet beta-cell, characterized by low proliferative potential, is normally not responsive to the polypeptid e epidermal growth factor (EGF) or its homolog transforming growth fac tor alpha (TGF-alpha). Since EGF receptors in other tissues can be up- regulated by other growth factors and by cytokines, we have in this pa per investigated whether such a beta-cell responsiveness to TGF-alpha, or EGF, can be conferred by co-culture with interferon gamma (IFN-gam ma), tumor necrosis factor alpha (TNF-alpha) or transforming growth fa ctor beta (TGF-beta) in various combinations. To this end, fetal rat p ancreatic islets enriched in beta-cells were isolated and cultured for 3 days with or without 200 pM or 20 nM TGF-alpha. It was found that n either of these TGF-alpha concentrations affected beta-cell mitogenesi s, insulin content or insulin secretion. However, IFN-gamma (1000 U/ml ) evoked a modest stimulation of beta-cell replication, while suppress ing insulin secretion and leaving the islet insulin content unaltered, TNF-alpha (1000 U/ml), on the other hand, affected none of these para meters either alone or in any combination with TGF-alpha or IFN-gamma. However, when TNF-alpha or IFN-gamma, either alone or in combination, were combined with the cytokine interleukin-1 beta, this resulted in islet disintegration, whereas the latter cytokine alone did not exert any gross necrotic changes evident by light microscopy. TGF-beta (500 pM) stimulated insulin secretion but did not influence islet insulin c ontent or beta-cell mitogenesis either alone or in combination with TG F-alpha (200 pM or 20 nM). In no instance could any mitogenic or secre tory response to low or high concentrations of TGF-alpha be conferred by IFN-gamma, TNF-alpha or TGF-beta whether used alone or in combinati ons. Hence, responsiveness to TGF-alpha or EGF in the beta-cell obviou sly cannot be achieved by any of these peptides.