IL-1β, IFN-γ and TNF-α increase vulnerability of pancreatic beta cells to autoimmune destruction

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• 作者：Wachlin ; Gerhild ; Augstein ; Petra ; Schrö ; der ; Dieter ; Kuttler ; Beate ; Klö ; ting ; Ingrid ; et. al.
• 关键词：Diabetes ; Pancreatic β ; -cell ; Apoptosis ; Fas receptor ; ICAM-1 ; BB rat ; Cytokines ; IL-1β ; IFN-γ ; TNF-&#945 ; IL-1β ; interleukin-1β ; IFN-γ ; interferon-γ ; TNF-&#945 ; tumour necrosis factor-&#945 ; FADD ; Fas-associating prot
• 刊名：Journal of Autoimmunity
• 出版年：2003
• 出版时间：June, 2003
• 年：2003
• 卷：20
• 期：4
• 页码：303-312
• 全文大小：199 K

文摘

In the pathogenesis of type-1 diabetes insulin-producing β-cells are destroyed by cellular autoimmune processes. The locality of β-cell destruction is the inflamed pancreatic islet. During insulitis cytokines released from islet-infiltrating mononuclear cells affect β-cells at several levels. We investigated whether cytokine-induced β-cell destruction is associated with changes in the expression of the surface receptors intercellular adhesion molecule (ICAM)-1 and Fas. Islets from diabetes-prone and congenic diabetes-resistant BB rats were exposed to interleukin (IL)-1β alone or in combination with interferon (IFN)-γ plus tumour necrosis factor (TNF)-α. Cytokines decreased islet insulin content, suppressed glucose stimulated insulin secretion and generated enhanced amounts of nitric oxide and DNA-strand breaks. While no membrane alterations of IL-1β treated islets cells were detectable, the cytokine combination caused damage of cell membranes. Independent of diabetes susceptibility IL-1β treated islet β-cells expressed a significantly increased amount of ICAM-1 on their surfaces which was not further increased by IFN-γ+TNF-α. However, IL-1β induced Fas expression was significantly enhanced only on β-cells from diabetes-prone BB rats. From these results we suggest that IL-1β mediates the major stimulus for ICAM-1 induction which is possibly a necessary but not sufficient step in the process of β-cell destruction. Obviously, the additional enhancement of Fas expression on the surface of β-cells is important for destruction. The combined action of all three cytokines induced the expression of Fas on the β-cell surface independent of diabetes susceptibility, indicating that such a strong stimulus in vitro may induce processes different from the precise mechanisms of β-cell destruction in vivo.