Baker Marshall S, Chen Xiaojuan, Rotramel Alizah R, Nelson Jeffrey J, Kaufman Dixon B
Department of Surgery, Division of Organ Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Surgery. 2003 Aug;134(2):134-41. doi: 10.1067/msy.2003.236.
Interferon (IFN)-gamma acts synergistically with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha to activate isoform of nitric oxide synthetase (iNOS) gene expression, induce apoptosis, and impair glucose-stimulated insulin release (GSIR) in pancreatic islets. This effect is an important mechanism of islet dysfunction in models of pancreatitis, type I diabetes, and islet allograft rejection. We tested the hypothesis that transcription factor interferon regulatory factor (IRF)-1 plays a regulatory role in both this cytokine-induced islet injury and cytokine-induced gene expression for chemotactic chemokines.
Isolated islets from wild-type (WT) or IRF-1(-/-) C57BL/6 mice were cultured in a mixture of IL-1beta, TNF-alpha, and IFN-gamma +/- the iNOS inhibitor L-NMMA. The following end points were assessed: i) GSIR; ii) rates of apoptosis; and iii) gene expression for iNOS, IRF-1 and inducible protein (IP)-10, monocyte chemoattractive protein (MCP)-1, macrophage inflammatory protein-1alpha, and macrophage inflammatory protein-1beta.
Cytokine-treated WT islets demonstrated an increase in IRF-1 and iNOS gene expression, inhibition of GSIR, increased rates of apoptosis, and increased gene transcription and protein release for IP-10 and MCP-1. Cytokine-treated IRF-1(-/-) islets demonstrated relatively less iNOS gene expression, preserved GSIR, reduced rates of apoptosis, and a more marked increase in transcription for IP-10 and MCP-1 and in IP-10 protein release. L-NMMA-cotreated WT islets were completely resistant to cytokine-induced dysfunction and apoptosis but demonstrated the same degree of cytokine-induced chemokine gene expression as cytokine-treated WT without L-NMMA.
IFN-gamma, IL-1beta, and TNF-alpha in combination induce chemokine gene expression in pancreatic islets. Transcription factor IRF-1 mediates cytokine-induced islet dysfunction, apoptosis, and iNOS gene expression but down-regulates IP-10 gene expression.
干扰素（IFN）-γ与白细胞介素（IL）-1β和肿瘤坏死因子（TNF）-α协同作用，激活一氧化氮合酶（iNOS）基因表达的异构体，诱导细胞凋亡，并损害胰腺胰岛中葡萄糖刺激的胰岛素释放（GSIR）。这种效应是胰腺炎、I型糖尿病和胰岛移植排斥模型中胰岛功能障碍的重要机制。我们检验了转录因子干扰素调节因子（IRF）-1在这种细胞因子诱导的胰岛损伤和趋化性趋化因子的细胞因子诱导基因表达中均起调节作用的假说。
将野生型（WT）或IRF-1（-/-）C57BL/6小鼠分离的胰岛在IL-1β、TNF-α和IFN-γ的混合物中培养，并添加或不添加iNOS抑制剂L-NMMA。评估以下终点：i）GSIR；ii）细胞凋亡率；iii）iNOS、IRF-1和诱导性蛋白（IP）-10、单核细胞趋化蛋白（MCP）-1、巨噬细胞炎性蛋白-1α和巨噬细胞炎性蛋白-1β的基因表达。
细胞因子处理的WT胰岛显示IRF-1和iNOS基因表达增加，GSIR受到抑制，细胞凋亡率增加，IP-10和MCP-1的基因转录和蛋白释放增加。细胞因子处理的IRF-1（-/-）胰岛显示iNOS基因表达相对较少，GSIR得以保留，细胞凋亡率降低，IP-10和MCP-1的转录以及IP-10蛋白释放有更明显的增加。L-NMMA共同处理的WT胰岛对细胞因子诱导的功能障碍和细胞凋亡完全有抗性，但与未添加L-NMMA的细胞因子处理的WT胰岛相比，显示出相同程度的细胞因子诱导的趋化因子基因表达。
IFN-γ、IL-1β和TNF-α联合诱导胰腺胰岛中的趋化因子基因表达。转录因子IRF-1介导细胞因子诱导的胰岛功能障碍、细胞凋亡和iNOS基因表达，但下调IP-10基因表达。
