RECOMBINANT HUMAN TRANSFORMING GROWTH-FACTOR-BETA DOES NOT INHIBIT THE EFFECTS OF INTERLEUKIN-1-BETA ON PANCREATIC-ISLET CELLS

The macrophage-derived cytokine, interleukin-1 beta (IL-1 beta), has b een implicated to play an important role in the autoimmune beta cell l esion of insulin-dependent diabetes mellitus (IDDM) because of its inh ibition of insulin secretion, direct cytotoxicity, and alteration of i slet cell antigen expression. Because transforming growth factor beta (TGF-beta) has been reported to inhibit IL-1 receptor expression in se veral lymphoid and progenitor cell lines, to induce IL-1 receptor anta gonist protein (IRAP) production in human peripheral blood monocytes, and to antagonize several effects of inflammatory cytokines and becaus e oral tolerance may be mediated in part by TGF-P released by regulato ry T lymphocytes, we investigated whether TGF-beta counteracted the ef fects of IL-1 beta on islet cells. Islets isolated from Sprague-Dawley rats were cultured with or without recombinant human IL-1 beta and TG F-beta. Accumulated insulin secretion, cytokine-induced cytotoxicity, and islet cell expression of glutamic acid decarboxylase 65 (GAD-65) a nd heat-shock protein 70 (HSP-70) were measured in this study. We foun d that (1) IL-1 beta at 50 and 100 pg/ml inhibited insulin secretion b y 41.9 +/- 14.8 and 52.6 +/- 3.5% and induced cytotoxicity by 45.5 +/- 17.3 and 54.1 +/- 6.1%, respectively. IL-1 beta at 1000 pg/ml signifi cantly increased HSP-70 expression and decreased GAD-65 expression. (2 ) TGF-beta at 0.1, 1, 10, and 40 ng/ml had no significant effect on in sulin secretion and did not induce cytotoxicity, TGF-beta at 40 ng/ml had no effect on the expression of either HSP-70 or GAD-65. (3) In com bination, TGF-beta at 1, 10, and 40 ng/ml did not antagonize the IL-1 beta (50 and 100 pg/ml)-induced inhibition of insulin secretion or cyt otoxicity; TGF-beta (40 ng/ml) did not block the effects of IL-1 beta (1000 pg/ml) on HSP-70 or GAD-65 expression. In conclusion, recombinan t human TGF-beta does not counteract these effects of recombinant huma n IL-1 beta on rat pancreatic islet cells.