Pancreatic β-Cell–Selective Production of Tumor Necrosis Factor-α Induced by Interleukin-1

Abstract

Cytokines have been regarded as effector molecules responsible for beta-cell death and major histocompatibility complex hyperexpression in endocrine pancreas of type I diabetes. However, the mechanism that results in beta-cell-selective destruction has not been elucidated. We demonstrated in this study, using cell lines of transformed mouse beta-cells and alpha-cells, that only pancreatic beta-cells but not alpha-cells produced tumor necrosis factor-alpha when exposed to interleukin-1 beta. Northern blot analysis confirmed the beta-cell-selective expression of tumor necrosis factor-alpha mRNA. Interleukin-1 beta also provoked tumor necrosis factor-alpha mRNA expression in vitro by normal mouse islet cells. Because tumor necrosis factor-alpha has been shown to potentiate beta-cell cytotoxicity of interleukin-1 and interferon-gamma, tumor necrosis factor-alpha produced in situ by beta-cells might be self-destructive. In fact, a low dose of interleukin-1 beta in combination with a low dose of interferon-gamma preferentially injured beta-cells. Hence endogenous tumor necrosis factor-alpha production by beta-cells may be involved in beta-cell-selective destruction in type 1 diabetes.

Cytokine-mediated Down-regulation of the Transcription Factor cAMP-response Element-binding Protein in Pancreatic β-Cells

“…For example, IL-1␤ increases the production of TNF-␣ by ␤-cells thereby exaggerating cytotoxicity (54). IL-1␤, synthesized as an inactive precursor, is cleaved and activated by interleukin-1-converting enzyme, the expression of which is induced by IFN-␥ in pancreatic islets (55).…”

Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset Type I diabetes mellitus

“…Although the reason is not clear, such a possibility has been raised by the results of several experiments. The beta cells produced inducible nitric oxide synthase or TNF-a or both more efficiently than alpha cells by the stimulation of cytokines [39,40]. Mouse insulinoma-derived cell line, bTC1, was more susceptible to cytokine-induced apoptosis than glucagonoma-derived cell line, aTC1, Mù, Macrophages; ND, not determined; a Case 16 is not included in the Total due to the lack of CD4 data probably because of lower endogenous Bcl-2 expression in bTC1 [41].…”

The potential role of cell adhesion molecules in the pathogenesis of diabetic neuropathy

“…Increased expression of CAMs enhances the ªstickinessº of the endothelium to cellular components of the bloodstream, most specifically monocytes [25]. Monocytes are activated by exposure to the increased levels of cytokines in the plasma of diabetic patients [26], resulting in increased expression of growth factors, cytokines and free radicals damaging the endothelium leading to platelet adhesion and thrombus formation as well as stimulating vascular smooth muscle cell proliferation [25]. Histopathological examination of diabetic nerve capillaries has demonstrated occlusion of blood vessels with endothelial cell hyperplasia and thickening of the capillary basement membrane with a reduction in capillary lumen [16].Measurement of nerve oxygen tension in sural nerves of diabetic patients with neuropathy has shown this to be significantly lower when compared to non-neuropathic subjects [27].…”