Recombinant human transforming growth factor beta does not inhibit the effects of interleukin-1 beta on pancreatic...

The macrophage-derived cytokine, interleukin-1 beta (IL-1 beta), has been implicated to play an important role in the autoimmune beta cell lesion of insulin-dependent diabetes mellitus (IDDM) because of its inhibition of insulin secretion, direct cytotoxicity, and alteration of islet cell antigen expression. Because transforming growth factor beta (TGF-beta) has been reported to inhibit IL-1 receptor expression in several lymphoid and progenitor cell lines, to induce IL-1 receptor antagonist protein (IRAP) production in human peripheral blood monocytes, and to antagonize several effects of inflammatory cytokines and because oral tolerance may be mediated in part by TGF-beta released by regulatory T lymphocytes, we investigated whether TGF-beta counteracted the effects of IL-1 beta on islet cells. Islets isolated from Sprague-Dawley rats were cultured with or without recombinant human IL-1 beta and TGF-beta. Accumulated insulin secretion, cytokine-induced cytotoxicity, and islet cell expression of glutamic acid decarboxylase 65 (GAD-65) and heat-shock protein 70 (HSP-70) were measured in this study. We found that (1) IL-1 beta at 50 and 100 pg/ml inhibited insulin secretion by 41.9 +/- 14.8 and 52.6 +/- 3.5% and induced cytotoxicity by 46.5 +/- 17.3 and 54.1 +/- 6.1%, respectively. IL-1 beta at 1000 pg/ml significantly 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 insulin 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 combination, 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 cytotoxicity; 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, recombinant human TGF-beta does not counteract these effects of recombinant human IL-1 beta on rat pancreatic islet cells.