Peptidergic Cells in Mouse Langerhans Islets Express TNFα

Introduction

Tumor necrosis factor (TNF)-α is a soluble or membrane-bound cytokine mainly expressed by monocytes and T-lymphocytes in response to a number of stimuli including bacterial and viral infections [1] [2] [3] [4]. TNFα has been shown to exert several effects on its target cells by binding to specific receptors. These effects include cytotoxic and cytostatic as well as proinflammatory and immunomodulatory actions [5] [6]. In addition, a number of experiments has shown that TNFα is able to influence secretory processes in the pancreatic islets in different species. Furthermore, it is heavily involved in modulating the course of autoimmune processes in Type I diabetes [6] [7].

Experiments with islet cultures and insulinoma cell lines have shown that TNFα is able to modulate insulin secretion [6] [8], to induce cytotoxicity or to enhance cytotoxic effects of other cytokines, especially interleukin-1β [7]. These effects could be blocked with IRAP (IL-1 receptor antagonist protein) and arginine analogs (N-monomethyl-l-arginine), indicating that the deleterious effects of TNFα are mediated by iNOS-induction (inducible form of nitric oxide synthase) and NO formation [9] [10].

So far, little is known about cytokine expression by endocrine cells in normal Langerhans islets. Cavallo et al. [11] found that viral infections trigger cytokine expression in a human insulinoma cell line (HIN). Mumps, rubella and measles infection each induced raised IL-6 levels that were detectable in the culture supernatant. The same experiments demonstrated that mumps and measles virus triggered IL-1β production by HIN cells. Yamada et al. [12] established that only pancreatic β-cells, but not α-cells, were capable of producing TNFα when exposed to recombinant human IL-1β using two cell lines derived from a transgenic mouse model. Toyoda et al. [13] detected TNFα encoding mRNA with RT-PCR (reverse transcriptase-polymerase chain reaction) in the islets of C57 mice at comparatively high levels. Similar observations were made in prediabetic and diabetic NOD mice (non-obese diabetic), indicating that TNFα expression in the pancreatic islet may be independent from the stage of insulitis during diabetes development in the NOD mice. Cytokines may be involved in the induction of apoptosis in endocrine islet cells. They may therefore be among the triggers of type I diabetes (for review, see [25]).

The aim of the present study was to investigate TNFα expression on the single-cell level in pancreatic islets in vivo and to correlate this with the peptide immunostaining pattern in order to determine the hormonal specificity of these cells. Thus, consecutive semithin sections of mouse pancreas were stained for islet hormones, TNFα and TNFα in situ hybridization. Special attention was paid to possible differences of immunoreactive patterns in young and old animals from two different mouse strains.

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