Effect of Cytokines on Beta Cell Function

细胞因子如白细胞介素-1 β（IL-1）、肿瘤坏死因子-α（TNF）和干扰素-γ（IFN）对胰岛细胞有深远的影响：1）它们抑制β细胞的胰岛素合成和分泌，2）它们破坏β细胞，和3）它们由I型糖尿病（IDDM）的胰岛炎中浸润胰岛的免疫和炎性细胞产生，以及在移植胰岛的免疫排斥过程中。这些研究的基本原理是，鉴定介导甜菜碱诱导的β细胞死亡的分子机制将促进新的预防和治疗策略的开发。因此，该项目的长期目标是了解参与I型糖尿病发病机制的甜菜碱诱导的β细胞死亡的机制。特别地，IL-1已显示抑制胰岛素生物合成和分泌、氧化代谢，并导致β细胞死亡。然而，一个关键问题是IL-1是否可以诱导β细胞凋亡和/或坏死。我们的初步数据表明，IL-1诱导胰岛素分泌β细胞系的凋亡。此外，我们已经表明，IL-1刺激2应激激活激酶的活性：p38和JNK。我们希望确定p38和JNK是否是细胞因子诱导的β细胞死亡所必需的，以及显性失活突变体的表达是否能阻止IL-1诱导的β细胞死亡。我们还发现了一种新的分泌细胞因子的存在下，唯一存在于胰岛。这种新的细胞因子定义了一类新的细胞因子。一个主要目标是阐明其在糖尿病发病机制中的作用。以下3个目标将阐述马槟榔碱诱导的β细胞死亡的机制。目的1：确定细胞因子诱导的β细胞死亡是由于坏死还是凋亡。将使用形态学、生物化学和细胞生物学技术的组合来解决这个问题。目的2：确定p38 JNK的激活是否是马槟榔碱诱导的β细胞死亡所必需的。将生成表达p38、JNK和激酶失活突变体的稳定β细胞系，并研究其对细胞因子的应答。目的3：阐明新的胰岛特异性细胞因子在β细胞功能方面的作用。

Cytokines such as interleukin-1beta (IL-1), tumor necrosis factor-alpha (TNF), and interferon-gamma (IFN) have profound effects on islet cells: 1) they inhibit insulin synthesis and secretion by the beta cell, 2) they destroy beta-cells, and 3) they are produced by immune and inflammatory cells infiltrating islets in the insulitis of type I diabetes mellitus (IDDM), and in the course of immune rejection of transplanted islets. The rationale for these studies is that the identification of the molecular mechanisms mediating cytokine-induced beta-cell death will facilitate the development of novel preventive and therapeutic strategies. Thus, the long-term goal of this project is to understand the mechanisms of cytokine-induced beta-cell death, involved in the pathogenesis of type I diabetes. In particular, IL-1 has been shown to inhibitor insulin biosynthesis and secretion, oxidative metabolism, and results in beta-cell death. However, a key question is whether IL-1 can induce apoptosis and/or necrosis of beta-cells. Our preliminary data suggest that IL-1 induces apoptosis in insulin-secreting beta-cell lines. In addition, we have shown that IL-1 stimulates the activity of 2 stress-activated kinases: p38 and JNK. We wish to determine whether p38 and JNK is necessary for cytokine- induced beta-cell death, and can expression of dominant-negative mutants prevent IL-1 induced beta-cell death. We have also discovered the presence of a novel secretory cytokine uniquely present in the islets of Langerhans. This novel cytokine defines a new class of cytokine. A major goal is to elucidate its role in the pathogenesis of diabetes. The following 3 aims will address the mechanisms of cytokine-induced beta-cell death. Aim 1: To determine whether cytokines-induced beta-cell death is due to necrosis or apoptosis. A combinations of morphological, biochemical and cell biological techniques will be used to address this issue. Aim 2: To determine whether activation of p38 JNK is required for cytokine-induced beta-cell death. Stable beta-cell lines expressing p38, JNK, and kinase-inactive mutants will be generated and studied of their response to cytokine. Aim 3: To elucidate the role of the novel islet-specific cytokine in respect to beta-cell function.