Effect of Cytokines on Beta Cell Function

细胞因子如白介素1、肿瘤坏死因子和干扰素对胰岛细胞有深远的影响：1)它们抑制胰岛细胞的胰岛素合成和分泌；2)它们破坏胰岛细胞；3)它们是由免疫细胞和炎症细胞在I型糖尿病(IDDM)的胰岛炎症和移植胰岛免疫排斥反应过程中产生的。这些研究的基本原理是，识别介导细胞因子诱导的β细胞死亡的分子机制将有助于开发新的预防和治疗策略。因此，该项目的长期目标是了解细胞因子诱导的β细胞死亡的机制，这涉及到I型糖尿病的发病机制。特别是，IL-1已被证明抑制胰岛素的生物合成和分泌，氧化代谢，并导致β细胞死亡。然而，一个关键的问题是IL-1是否能诱导β细胞的凋亡和/或坏死。我们的初步数据表明，IL-1诱导胰岛素分泌的β细胞系发生凋亡。此外，我们还发现IL-1可以刺激两种应激激活的蛋白激酶：p38和JNK的活性。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-负性突变体的表达能否阻止IL-1诱导的β细胞死亡。我们还发现了一种新的分泌性细胞因子的存在，这种细胞因子独特地存在于朗格汉斯的胰岛中。这种新的细胞因子定义了一类新的细胞因子。一个主要的目标是阐明它在糖尿病发病机制中的作用。以下三个目标将解决细胞因子诱导的β细胞死亡的机制。目的1：确定细胞因子诱导的胰岛β细胞死亡是由于坏死还是细胞凋亡。将综合运用形态、生化和细胞生物学技术来解决这一问题。目的2：确定细胞因子诱导的β细胞死亡是否需要激活p38JNK。表达p38、JNK和激酶失活突变体的稳定的β细胞系将被建立，并研究它们对细胞因子的反应。目的3：阐明新型胰岛特异性细胞因子在胰岛β细胞功能中的作用。

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.