PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist.
PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist.
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DOI：
10.1038/labinvest.2013.133
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发表时间：
2014-01
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--
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越来越多的人担心接受长期GLP-1类似物治疗的糖尿病患者发生胰腺炎。其发病机制尚不清楚。GLP-1激动剂对胰腺内分泌细胞的影响已得到充分研究，但对可能参与炎症过程的其他胰腺组织的影响信息很少。胰腺星状细胞（Pancreatic stellate cells，PSC）在胰腺炎中发挥重要作用，分泌多种炎症细胞因子/趋化因子以及胶原蛋白。在这项研究中，我们研究了GLP-1 R在正常胰腺、急性/慢性胰腺炎中的发生，以及GLP-1类似物对正常PSC的影响，其刺激炎症介质分泌或增殖的能力。采用组织学/免疫组织化学分析评价了正常胰腺和胰腺炎（急性/慢性）组织中GLP-1 R的表达/定位。PSC分离自雄性Wistar大鼠。用实时PCR、MTS测定和Western印迹检测GLP-1类似物对活化的PSC的GLP 1 R表达和作用。在正常胰腺中，胰腺β细胞表达GLP-1 R，仅在腺泡细胞中低表达，而在急性或慢性胰腺炎中，腺泡细胞、导管细胞和活化的PSC表达GLP-1 R。随着正常PSC的活化，GLP-1 R显著增加，多种其他肠促胰岛素相关受体也是如此。GLP-1类似物利拉鲁肽在活化的PSC中不诱导炎症基因表达，但诱导增殖。利拉鲁肽激活PSC中的多个信号级联，ERK通路介导PSC增殖。GLP-1 Rs在正常胰腺中表达，在急性/慢性胰腺炎中表达明显增强。GLP-1激动剂诱导活化PSC的细胞增殖，而不增加炎症介质的释放。这些结果表明，GLP-1 R激动剂长期给药可能导致PSC增殖/慢性活化，这可能对胰腺产生重要影响。
There is increasing concern about the development of pancreatitis in patients with diabetes mellitus who received long-term GLP-1 analog treatment. Its pathogenesis is unknown. The effects of GLP-1 agonists on pancreatic endocrine cells is well studied, however there is little information on effects on other pancreatic tissues that might be involved in inflammatory processes. Pancreatic stellate cells (PSCs) can play an important role in pancreatitis, secreting various inflammatory cytokines/chemokines, as well as collagen. In this study, we investigated GLP-1R occurrence in normal pancreas, acute/chronic pancreatitis, and the effects of GLP-1 analog on normal PSCs, their ability to stimulate inflammatory mediator secretion or proliferation. GLP-1R expression/localization in normal pancreas and pancreatitis (acute/chronic) tissues were evaluated with histological/immunohistochemical analysis. PSCs were isolated from male Wistar rats. GLP1R expression and effects of GLP-1 analog on activated PSCs was examined with realtime PCR, MTS assays and Western Blotting. In normal pancreas, pancreatic β cells expressed GLP-1R, with only low expression in acinar cells, whereas in acute or chronic pancreatitis, acinar cells, ductal cells and activated PSCs expressed GLP-1R. With activation of normal PSCs, GLP-1R is markedly increased, as is multiple other incretin-related receptors. The GLP-1 analog, liraglutide, did not induce inflammatory genes expression in activated PSCs, but induced proliferation. Liraglutide activated multiple signaling cascades in PSCs, and the ERK pathway mediated the PSCs proliferation. GLP-1Rs are expressed in normal pancreas and there is marked enhanced expression in acute/chronic pancreatitis. GLP-1-agonist induced cell proliferation of activated PSCs without increasing release of inflammatory mediators. These results suggest chronic treatment with GLP-1R agonists could lead to proliferation/chronic activation of PSCs, which may lead to important effects in the pancreas.
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影响因子：
8.2
作者：
Butler, A. E.;Galasso, R.;Matveyenko, A.;Rizza, R. A.;Dry, S.;Butler, P. C.
通讯作者：
Butler, P. C.
影响因子：
29.4
作者：
Bachem, MG;Schneider, E;Adler, G
通讯作者：
Adler, G
影响因子：
4.8
作者：
Bullock, BP;Heller, RS;Habener, JF
通讯作者：
Habener, JF
影响因子：
29.4
作者：
Andoh, A;Takaya, H;Bamba, T
通讯作者：
Bamba, T
影响因子：
4
作者：
Friedrichsen, BN;Neubauer, N;Moldrup, A
通讯作者：
Moldrup, A