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| 購買進口儀器、試劑和耗材——就在始于2001年的畢特博生物 www.mobfastly.com |
最近，國際學術期刊Diabetologia在線發表了中科院上海生命科學研究院營養所樂穎影研究組的最新研究成果：TNF-α acutely upregulates amylin expression in murine pancreatic beta cells。這項工作主要由博士生蔡坤等在樂穎影研究員的指導下完成。 胰淀素(amylin)，又稱胰島淀粉樣多肽(islet amyloid polypeptide)，最初是從2型糖尿病病人的胰島淀粉樣沉淀中分離發現的。胰淀素主要由胰島β細胞合成和分泌，具有控制食欲、抑制胃排空、抑制胰島素分泌等生理功能。離體和整體實驗表明，胰淀素能誘導胰島素抵抗、促進胰島b細胞凋亡，參與2型糖尿病的發生發展。近年來發現在急性胰腺炎、胰腺移植后發生排斥的病人、肥胖癥和胰島素抵抗癥患者，血漿胰淀素水平顯著升高，但其原因及機制尚不清楚。 炎性細胞因子（如TNF-α、MCP-1等）在上述疾病的胰腺組織或血循環中顯著升高，它們不僅在急性胰腺炎和移植排斥中發揮重要作用，還參與胰島素抵抗和糖尿病的發生發展。蔡坤等利用小鼠胰島b細胞株MIN6和原代培養小鼠胰島，研究了炎性細胞因子對胰淀素表達的影響。研究發現，TNF-α能夠顯著上調胰淀素基因的表達，這種調節作用呈時間和濃度依賴性。TNF-α還能促進胰淀素蛋白的合成，主要以胰淀素前體蛋白及其酶切中間產物為主。通過生化和分子生物學的多種研究手段，他們進一步探討了TNF-α發揮調節作用的機制，發現TNF-α通過PKCζ-ERK1/2/JNK-AP1和PI3K-NF-κB相關信號通路上調胰淀素基因的表達。
炎性細胞因子TNF-α對胰淀素表達的上調作用及分子機制 此外還發現，TNF-α能顯著增強人胰淀素基因啟動子的活性，且這種調節作用由AP1和NF-κB介導，說明人胰淀素基因的表達和小鼠胰淀素基因一樣受TNF-α調節。這些結果提示在胰腺急性炎癥相關疾病中，炎性細胞因子除直接發揮作用外，還可能通過誘導胰淀素表達而促進疾病的發展，為進一步探討胰淀素的病理作用提供了新的線索。 此項工作得到國家科技部和上海市科委經費資助。 推薦原文出處： Diabetologia DOI 10.1007/s00125-010-1972-9 TNF-α 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. Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, and the Graduate School of the Chinese Academy of Sciences, Shanghai, People's Republic of China. Abstract 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-α is involved in these disorders. We investigated the effect of TNF-α 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 κB (NF-κB) 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-α 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 Cζ [Formula: see text], (2) MIN6 cells expressing a c-Jun-dominant negative construct and (3) islets from Fos knockout mice demonstrated that TNF-α induced amylin expression through the [Formula: see text] signal-regulated kinase (ERK)/JNK pathways. EMSA showed that [Formula: see text], JNK and ERK1/2 were involved in TNF-α-induced AP1 activation, suggesting that TNF-α induces murine amylin expression through the [Formula: see text] and [Formula: see text] pathways. Further studies showed that TNF-α also induced murine amylin expression through the phosphatidylinositol 3 kinase-NF-κB signalling pathway and enhanced human amylin promoter activation through NF-κB and AP1. CONCLUSIONS/INTERPRETATION: TNF-α acutely induces amylin gene expression in beta cells through multiple signalling pathways, possibly contributing to amylin elevation in acute inflammation-related pancreatic disorders. |
購買進口儀器、試劑和耗材——就在始于2001年的畢特博生物
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