MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2.
<h4>Background</h4>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 resist...
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2011
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oai:doaj.org-article:f2d75063f2704988984e0f98dfcbdb7d2021-11-18T06:54:09ZMCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2.1932-620310.1371/journal.pone.0019559https://doaj.org/article/f2d75063f2704988984e0f98dfcbdb7d2011-05-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21589925/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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.Kun CaiDongfei QiXinwei HouOumei WangJuan ChenBo DengLihua QianXiaolong LiuYingying LePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 5, p e19559 (2011) |
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Medicine R Science Q Kun Cai Dongfei Qi Xinwei Hou Oumei Wang Juan Chen Bo Deng Lihua Qian Xiaolong Liu Yingying Le MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. |
| description |
<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions/significance</h4>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. |
| format |
article |
| author |
Kun Cai Dongfei Qi Xinwei Hou Oumei Wang Juan Chen Bo Deng Lihua Qian Xiaolong Liu Yingying Le |
| author_facet |
Kun Cai Dongfei Qi Xinwei Hou Oumei Wang Juan Chen Bo Deng Lihua Qian Xiaolong Liu Yingying Le |
| author_sort |
Kun Cai |
| title |
MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. |
| title_short |
MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. |
| title_full |
MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. |
| title_fullStr |
MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. |
| title_full_unstemmed |
MCP-1 upregulates amylin expression in murine pancreatic β cells through ERK/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. |
| title_sort |
mcp-1 upregulates amylin expression in murine pancreatic β cells through erk/jnk-ap1 and nf-κb related signaling pathways independent of ccr2. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/f2d75063f2704988984e0f98dfcbdb7d |
| work_keys_str_mv |
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