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 polypeptide epidermal growth factor (EGF) or its homolog transforming growth factor alpha (TGF-alpha). Since EGF receptors in other tissues can be up-regulated by other growth factors and by cytokines, we have in this paper investigated whether such a beta-cell responsiveness to TGF-alpha, or EGF, can be conferred by co-culture with interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha) or transforming growth factor beta (TGF-beta) in various combinations. To this end, fetal rat pancreatic 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 neither of these TGF-alpha concentrations affected beta-cell mitogenesis, insulin content or insulin secretion. However, IFN-gamma (1000 U/ml) evoked a modest stimulation of beta-cell replication, while suppressing insulin secretion and leaving the islet insulin content unaltered. TNF-alpha (1000 U/ml), on the other hand, affected none of these parameters 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 content or beta-cell mitogenesis either alone or in combination with TGF-alpha (200 pM or 20 nM). In no instance could any mitogenic or secretory response to low or high concentrations of TGF-alpha be conferred by IFN-gamma. TNF-alpha or TGF-beta whether used alone or in combinations. Hence, responsiveness to TGF-alpha or EGF in the beta-cell obviously cannot be achieved by any of these peptides.
Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, Karolinska Hospital, Stockholm, Sweden.
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Sjöholm
D000818:Animals; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007371:Interferon-gamma / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007328:Insulin; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D004247:DNA