Cytokine-induced osteoprotegerin expression protects pancreatic beta cells through p38 mitogen-activated protein kinase signalling against cell death
Cytokine-induced osteoprotegerin expression protects pancreatic beta cells through p38 mitogen-activated protein kinase signalling against cell death
复制标题
DOI：
10.1007/s00125-007-0672-6
复制
发表时间：
2007-04
期刊：
影响因子：
8.2
通讯作者：
J. Schrader;W. Rennekamp;U. Niebergall;M. Schoppet;H. Jahr;M. Brendel;D. Hörsch;L. Hofbauer
中科院分区：
文献类型：
--
作者：
J. Schrader;W. Rennekamp;U. Niebergall;M. Schoppet;H. Jahr;M. Brendel;D. Hörsch;L. Hofbauer
目的/假设促炎细胞因子在免疫介导的β细胞破坏中发挥关键作用，这是1型糖尿病发病机制中的一个基本机制。最近，基因芯片分析发现，护骨素(OPG；现在称为肿瘤坏死因子受体超家族，成员11b[TNFRSF11B])是β细胞中的一个细胞因子诱导基因。本研究的目的是研究OPG在细胞因子诱导的胰岛细胞死亡中的功能作用和信号转导途径。材料与方法以大鼠胰岛β细胞株INS-1E和人原代胰岛为细胞模型。用Northern印迹和免疫分析法检测IL-1β和肿瘤坏死因子-α对OPG表达的影响。四甲基偶氮唑蓝(3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyltetrazolium)比色法检测成骨蛋白对β细胞存活的影响。用p38丝裂原活化蛋白激酶、c-jun氨基末端激酶和细胞外信号调节激酶1/2的抗体进行免疫印迹分析。结果IL-1β和肿瘤坏死因子-α均能促进INS-1E细胞和原代胰岛表达OPGmRNA和分泌OPG蛋白。暴露于IL-1β可导致INS-1E细胞中p38MAPK的持续磷酸化和随后的细胞死亡。外源性OPG可阻止IL-1β诱导的β细胞死亡和持续的p38MAPK磷酸化。结论/解释我们的数据表明，细胞因子诱导的OPG的产生可能保护β细胞免受进一步的损伤。这种保护作用至少部分是通过抑制p38MAPK的磷酸化来实现的。因此，OPG是β细胞的自分泌或旁分泌生存因子。
Aims/hypothesisPro-inflammatory cytokines play a crucial role in immune-mediated beta cell destruction, an essential mechanism in the pathogenesis of type 1 diabetes mellitus. Microarray analysis recently identified osteoprotegerin (OPG; now known as tumour necrosis factor receptor superfamily, member 11b [TNFRSF11B]) as a cytokine-induced gene in beta cells. The aim of the present study was to characterise the functional role and signalling pathways of OPG that are involved in cytokine-induced beta cell death.Materials and methodsAs cellular models, the rat beta cell line INS-1E and human primary pancreatic islets were employed. The effects of IL-1β and TNF-α onOPGexpression were characterised by northern blot and immunoassay. The effect of OPG on beta cell survival was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Signalling pathways were evaluated by western blot analysis using antibodies against p38 mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2.ResultsThe INS-1E cell line and primary pancreatic islets expressedOPGmRNA and secreted OPG protein, both of which were enhanced by IL-1β and TNF-α. Exposure to IL-1β resulted in sustained phosphorylation of p38 MAPK in INS-1E cells and subsequent cell death. Administration of exogenous OPG prevented both IL-1β-induced beta cell death and sustained p38 MAPK phosphorylation.Conclusions/interpretationOur data indicate that cytokine-induced production of OPG may protect beta cells from further damage. This protective effect is, at least in part, mediated through inhibition of p38 MAPK phosphorylation. Thus OPG is an autocrine or paracrine survival factor for beta cells.