TNF-alpha acutely upregulates amylin expression in murine pancreatic beta cells

	TNF-alpha acutely upregulates amylin expression in murine pancreatic beta cells
	Cai, K; Qi, D; Wang, O; Chen, J; Liu, X; Deng, B; Qian, L; Liu, X; Le, Y
刊名	DIABETOLOGIA
	2011
卷号	54 期号:3 页码:617-626
关键词	Amylin Beta cell Gene expression Islet amyloid polypeptide Pancreatic islet Signalling transduction TNF-alpha
通讯作者	Le, Y (reprint author), Chinese Acad Sci, Key Lab Nutr & Metab, Inst Nutr Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China.,yyle@sibs.ac.cn
英文摘要	Aims/hypothesis Amylin, a secretory protein mainly produced by pancreatic beta cells, is elevated in the circulation of patients with diseases related to acute and chronic inflammation, including acute pancreatitis, pancreas graft rejection, obesity and insulin resistance. TNF-alpha is involved in these disorders. We investigated the effect of TNF-alpha on amylin levels and the underlying mechanisms, using murine pancreatic beta cell line MIN6 and pancreatic islets. Methods Amylin, proinsulin and prohormone convertase 1/3, 2 (Pc1/3, Pc2 [also known as Pcsk1/3 and Pcsk2, respectively]) mRNA levels, and amylin promoter and nuclear factor kappa B (NF-kappa B) activation were examined by real-time PCR and luciferase reporter assay, respectively. Amylin protein level and mitogen-activated protein kinase phosphorylation were detected by western blot. Activator protein 1 (AP1) activation was examined by electrophoretic mobility shift assay (EMSA). Results TNF-alpha acutely induced amylin expression at the transcriptional level and increased proamylin and the intermediate form of amylin in MIN6 cells and islets. However, it had no effect on proinsulin, Pc1/3 and Pc2 expression. Studies with (1) MIN6 cells treated with inhibitors of MEK1/2, c-Jun-N-terminal kinase (JNK) or protein kinase C zeta (PKC(zeta)), (2) MIN6 cells expressing a c-Jun-dominant negative construct and (3) islets from Fos knockout mice demonstrated that TNF-alpha induced amylin expression through the PKC(zeta)-extracellular signal-regulated kinase (ERK)/JNK pathways. EMSA showed that PKC(zeta), JNK and ERK1/2 were involved in TNF-alpha-induced AP1 activation, suggesting that TNF-alpha induces murine amylin expression through the PKC(zeta)-ERK1/2-AP1 and PKC(zeta)- JNK-AP1 pathways. Further studies showed that TNF-alpha also induced murine amylin expression through the phosphatidylinositol 3 kinase-NF-kappa B signalling pathway and enhanced human amylin promoter activation through NF-kappa B and AP1. Conclusions/interpretation TNF-alpha acutely induces amylin gene expression in beta cells through multiple signalling pathways, possibly contributing to amylin elevation in acute inflammation-related pancreatic disorders.
学科主题	Endocrinology & Metabolism
类目[WOS]	Endocrinology & Metabolism
关键词[WOS]	ISLET AMYLOID POLYPEPTIDE ; DEPENDENT DIABETES-MELLITUS ; FACTOR-KAPPA-B ; INSULIN-RESISTANCE ; GENE-EXPRESSION ; TRANSPLANTATION ; ACTIVATION ; LANGERHANS ; PROTEIN ; MECHANISMS
收录类别	SCI
语种	英语
WOS记录号	WOS:000286987000019
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/766]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Cai, K,Qi, D,Wang, O,et al. TNF-alpha acutely upregulates amylin expression in murine pancreatic beta cells[J]. DIABETOLOGIA,2011,54(3):617-626.
APA	Cai, K.,Qi, D.,Wang, O.,Chen, J.,Liu, X.,...&Le, Y.(2011).TNF-alpha acutely upregulates amylin expression in murine pancreatic beta cells.DIABETOLOGIA,54(3),617-626.
MLA	Cai, K,et al."TNF-alpha acutely upregulates amylin expression in murine pancreatic beta cells".DIABETOLOGIA 54.3(2011):617-626.