Reddy Shiva, Ross Jacqueline M
School of Biological Sciences, Department of Pediatrics, University of Auckland, Auckland, New Zealand.
Ann N Y Acad Sci. 2003 Nov;1005:166-9. doi: 10.1196/annals.1288.019.
During insulin-dependent diabetes mellitus, beta cell destruction may involve activation of the Fas-Fas ligand (Fas-FasL) system. Here, we employed dual-label immunohistochemistry to examine the intra-islet expression, distribution, and cellular sources of Fas and FasL in the NOD mouse. Pancreatic tissues were studied during spontaneous diabetes (days 21, 40, and 90) and following acceleration of diabetes with cyclophosphamide (days 0, 4, 7, 11, and 14 after cyclophosphamide administration). Our results show that FasL was expressed constitutively in most beta cells of NOD mice and in nondiabetes-prone mice, but not in glucagon or somatostatin cells or in islet inflammatory cells. It paralleled the loss of insulin immunolabeling with advancing disease. Immunolabeling for Fas was first observed in extra-islet macrophages and those close to the islet in NOD and nondiabetes-prone mice. During spontaneous and cyclophosphamide diabetes, it was observed in a higher proportion of islet infiltrating macrophages than in CD4 and CD8 cells. In the cyclophosphamide group, Fas expression in intra-islet CD4 and CD8 cells showed an increase close to the onset of diabetes. At days 11 and 14, several intra-islet macrophages with immunolabeling for Fas also coexpressed interleukin-1beta and inducible nitric oxide synthase. Fas was not detected in beta cells and other endocrine cells during spontaneous and cyclophosphamide diabetes. We show constitutive expression of FasL in beta cells in the NOD mouse and predominant expression of Fas in intra-islet macrophages and to a lesser extent in T cells prior to diabetes onset. The role of Fas-FasL in beta cell destruction in the NOD mouse requires further clarification.
在胰岛素依赖型糖尿病期间，β细胞破坏可能涉及Fas-Fas配体（Fas-FasL）系统的激活。在此，我们采用双标免疫组织化学法来检测NOD小鼠胰岛内Fas和FasL的表达、分布及细胞来源。在自发性糖尿病期间（第21、40和90天）以及用环磷酰胺加速糖尿病进程后（环磷酰胺给药后第0、4、7、11和14天）对胰腺组织进行研究。我们的结果显示，FasL在NOD小鼠和非糖尿病易患小鼠的大多数β细胞中组成性表达，但在胰高血糖素或生长抑素细胞以及胰岛炎症细胞中不表达。它与随着疾病进展胰岛素免疫标记的丧失平行。在NOD小鼠和非糖尿病易患小鼠中，首先在胰岛外巨噬细胞以及靠近胰岛的巨噬细胞中观察到Fas免疫标记。在自发性和环磷酰胺诱导的糖尿病期间，胰岛浸润巨噬细胞中Fas表达的比例高于CD4和CD8细胞。在环磷酰胺组中，胰岛内CD4和CD8细胞中的Fas表达在糖尿病发病临近时增加。在第11和14天，几个Fas免疫标记的胰岛内巨噬细胞也共表达白细胞介素-1β和诱导型一氧化氮合酶。在自发性和环磷酰胺诱导的糖尿病期间，在β细胞和其他内分泌细胞中未检测到Fas。我们显示NOD小鼠β细胞中FasL的组成性表达以及糖尿病发病前胰岛内巨噬细胞中Fas的主要表达，在T细胞中的表达程度较低。Fas-FasL在NOD小鼠β细胞破坏中的作用需要进一步阐明。
