The destructive action of IL-1alpha and IL-1beta in IDDM is a multistage process: evidence and confirmation by apoptotic studies, induction of intermediates and electron microscopy.

S Vassiliadis,K Konidaris,E Protopapadakis,P Mitlianga,I Athanassakis,G K Papadopoulos,V Dragiotis

doi:10.1080/09629359990577

S Vassiliadis, K Konidaris + Show 5 more

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https://doi.org/10.1080/09629359990577

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Abstract

Using the rat beta-cell RIN-5AH insulinoma line as a means for studying insulin-dependent diabetes mellitus (IDDM), it is shown that interleukin-1 (IL-1) induces beta-cell damage initiated by early apoptotic signals. This action is demonstrated by DNA fragmentation, as assessed by specific BrdU labeling, surface expression of Fas and nitric oxide (NO) production. In addition, the interplay between NO and Fas is shown, while scanning electron microscopy (SEM) confirms apoptosis by revealing the degree and type of cellular damage which, in the case of IL-1alpha, can be reversed by an inhibitor to NO synthesis. Apoptosis is also reconfirmed by transmission electron microscopy (TEM) by observing condensed nuclear chromatin after IL-1 exposure. Thus, treatment of insulinoma cells with IL-1alpha and IL-1beta seems to initiate a number of signals, including PKC activation as published previously, that ultimately lead to beta-cell destruction. Each IL-1 isoform, however, definitely follows a different pathway of action.

Highlights

Insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease characterized by specific destruction of insulin-secreting b cells of the pancreas.[1,2] Pancreatic Langerhans islets are composed of a heterogeneous population of secretory cells as well as non-endocrine cells.[3]
One major finding is the ability of non-endocrine cells, mainly activated macrophages, natural killer (NK) cells, as well as B and T lymphocytes, to produce diverse cytokines like interleukin-1 (IL-1a, IL-1b ), tumor necrosis factor-a (TNF-a ) and interferon-g (IFN-g ).[11,12,13]
This approach permitted to demonstrate that both IL-1a and IL-1b initiated an early apoptotic signal, as detected by cytoplasmic DNA fragmentation, that was maximal 4 h after cytokine addition (Fig. 1B,C)

Summary

Introduction

Insulin-dependent diabetes mellitus (IDDM) is a chronic autoimmune disease characterized by specific destruction of insulin-secreting b cells of the pancreas.[1,2] Pancreatic Langerhans islets are composed of a heterogeneous population of secretory cells (a and b cells) as well as non-endocrine cells (macrophages, endothelial cells, dendritic cells and fibroblasts).[3] The presence of such a variety of cellular components renders the investigation of causes leading to b cell destruction extremely difficult and, studies on IDDM started decades ago,[4] the exact pathway(s) from insulitis to the end-stage disease still remains unknown.[5,6,7]. One major finding is the ability of non-endocrine cells, mainly activated macrophages, natural killer (NK) cells, as well as B and T lymphocytes, to produce diverse cytokines like interleukin-1 (IL-1a , IL-1b ), tumor necrosis factor-a (TNF-a ) and interferon-g (IFN-g ).[11,12,13] These cytokines have been shown to induce b cells to undergo a number of

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