MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2.
MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2.
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DOI：
10.1371/journal.pone.0019559
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发表时间：
2011-05-11
期刊：
影响因子：
3.7
通讯作者：
Le Y
中科院分区：
文献类型：
--
作者：
Cai K;Qi D;Hou X;Wang O;Chen J;Deng B;Qian L;Liu X;Le Y
胰淀素是胰岛淀粉样蛋白中含量最丰富的成分，与2型糖尿病的发生有关。血浆胰淀素水平在肥胖和胰岛素抵抗个体中升高。单核细胞趋化蛋白-1（MCP-1，CCL 2）参与肥胖和2型糖尿病的胰岛素抵抗。我们研究了MCP-1对胰淀素表达的影响以及小鼠胰腺β细胞系MIN 6和胰岛的潜在机制。我们发现MCP-1在转录水平上诱导了MIN 6细胞和胰岛中胰淀素的表达，并在蛋白水平上增加了胰淀素原和中间形式的胰淀素。然而，MCP-1对胰岛素原1和2以及激素原转化酶（PC）1/3和PC 2的表达没有影响，表明MCP-1特异性地诱导β细胞中胰淀素的表达。机制研究表明，虽然在MIN 6细胞和胰岛中没有可检测到的CCR 2 mRNA，但用百日咳毒素预处理MIN 6细胞抑制了MCP-1诱导的胰淀素表达，表明替代性Gi偶联受体介导了MCP-1的诱导作用。MCP-1快速诱导ERK 1/2和JNK磷酸化。MEK 1/2（PD 98059）、JNK（SP 600125）或AP 1（姜黄素）的抑制剂显著抑制MCP-1诱导的胰淀素mRNA表达。MCP-1不能诱导胰岛中胰岛淀粉样多肽的表达，分离自Fos基因敲除小鼠。EMSA显示JNK和ERK 1/2参与了MCP-1诱导的AP 1活化。这些结果表明MCP-1通过ERK 1/2或JNK介导的AP 1活化诱导小鼠胰淀素表达。进一步的研究表明，用NF-κB抑制剂或过表达IκBα显性负性结构处理MIN 6细胞，可显著抑制MCP-1诱导的胰淀素表达，提示NF-κB相关信号通路也参与了MCP-1诱导的小鼠胰淀素表达。MCP-1通过ERK 1/2/JNK-AP 1和NF-κB相关信号通路诱导胰淀素表达，而不依赖于CCR 2。MCP-1上调胰淀素可能导致肥胖和胰岛素抵抗患者血浆胰淀素水平升高。
Amylin is the most abundant component of islet amyloid implicated in the development of type 2 diabetes. Plasma amylin levels are elevated in individuals with obesity and insulin resistance. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is involved in insulin resistance of obesity and type 2 diabetes. We investigated the effect of MCP-1 on amylin expression and the underlying mechanisms with murine pancreatic β-cell line MIN6 and pancreatic islets. We found that MCP-1 induced amylin expression at transcriptional level and increased proamylin and intermediate forms of amylin at protein level in MIN6 cells and islets. However, MCP-1 had no effect on the expressions of proinsulin 1 and 2, as well as prohormone convertase (PC) 1/3 and PC2, suggesting that MCP-1 specifically induces amylin expression in β-cells. Mechanistic studies showed that although there is no detectable CCR2 mRNA in MIN6 cells and islets, pretreatment of MIN6 cells with pertussis toxin inhibited MCP-1 induced amylin expression, suggesting that alternative Gi-coupled receptor(s) mediates the inductive effect of MCP-1. MCP-1 rapidly induced ERK1/2 and JNK phosphorylation. Inhibitors for MEK1/2 (PD98059), JNK (SP600125) or AP1 (curcumin) significantly inhibited MCP-1-induced amylin mRNA expression. MCP-1 failed to induce amylin expression in pancreatic islets isolated from Fos knockout mice. EMSA showed that JNK and ERK1/2 were involved in MCP-1-induced AP1 activation. These results suggest that MCP-1 induces murine amylin expression through AP1 activation mediated by ERK1/2 or JNK. Further studies showed that treatment of MIN6 cells with NF-κB inhibitor or overexpression of IκBα dominant-negative construct in MIN6 cells significantly inhibited MCP-1-induced amylin expression, suggesting that NF-κB related signaling also participates in MCP-1-induced murine amylin expression. MCP-1 induces amylin expression through ERK1/2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by MCP-1 may contribute to elevation of plasma amylin in obesity and insulin resistance.
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影响因子：
9.7
作者：
Hahm, ER;Cheon, G;Yang, CH
通讯作者：
Yang, CH
影响因子：
4.9
作者：
Kim, C-S;Park, H-S;Yu, R.
通讯作者：
Yu, R.
影响因子：
4.8
作者：
LANG, CH;DOBRESCU, C;BAGBY, GJ
通讯作者：
BAGBY, GJ
DOI：
10.1073/pnas.84.23.8628
发表时间：
1987-12-01
影响因子：
11.1
作者：
COOPER, GJS;WILLIS, AC;REID, KBM
通讯作者：
REID, KBM
影响因子：
2.4
作者：
Harsimran, Kaur;Singh, Arora Ajinder Pal;Vasudha, Sambyal
通讯作者：
Vasudha, Sambyal