Low-dose interleukin 1 and tumor necrosis factor individually stimulate insulin release but in combination cause suppression

Author:

Mehta Vivek K,Hao Wei,Brooks-Worrell Barbara M,Palmer Jerry P

Abstract

Mehta VK, Hao W, Brooks-Worrell BM, Palmer JP. Low-dose interleukin 1 and tumor necrosis factor individually stimulate insulin release but in combination cause suppression. Eur J Endocrinol 1994;130:208–14. ISSN 0804–4643 The macrophage-derived cytokines interleukin 1 (IL-1) and tumor necrosis factor (TNF) have direct effects on pancreatic beta cells and have been hypothesized to play important roles in the autoimmune beta cell lesion of type I diabetes because of two major effects on beta cells: altered insulin secretion and beta cell cytotoxicity. High doses of IL-1 are cytotoxic to beta cells and strongly inhibit insulin release; high-dose IL-1 plus TNF acts synergistically to suppress further the insulin release. In contrast, we observed that the predominant effect of low-dose IL-1 and TNF when administered separately was the stimulation of insulin release. We therefore asked whether the combination of low-dose IL-1 plus TNF would act synergistically to stimulate or suppress insulin release. Studies were performed on cultured rat islets and both insulin release and cytotoxicity (51Cr release) were measured. After 2 days of culture, increasing doses of IL-1—25, 50, 75 and 100 ng/l—caused progressively increased cytotoxicity and impaired insulin release. In contrast, the lowest dose of IL-1 tested, 10 ng/l, increased insulin release but was still slightly cytotoxic. Tumor necrosis factor at doses of 10, 25, 62.5, 75 and 100 μg/l also was slightly cytotoxic but increased insulin release. The augmented insulin release declined progressively with increasing TNF dose. However the combination of insulin stimulatory doses of IL-1 (10 ng/l) and TNF (62.5 μg/l) suppressed insulin release. The effects of these two cytokines on insulin release demonstrated a similar pattern after 4 and 6 days of culture. Although both IL-1 and TNF are cytotoxic to cultured islets cells, the effects of these two cytokines on insulin release are markedly different: with IL-1 primarily suppressing and TNF increasing insulin release. In combination, IL-1 and TNF always inhibits insulin release. The lack of concordance between insulin release and cytotoxicity suggests that these cytokines may alter insulin release by at least two mechanisms, one dependent on and the other independent of cytotoxicity. Jerry P Palmer, Veterans Affairs Medical Center, Endocrinology (111) ZB-21. 1660 S Columbian Way, Seattle, WA 98108, USA

Publisher

Bioscientifica

Subject

Endocrinology,General Medicine,Endocrinology, Diabetes and Metabolism

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