Statins Inhibit Inflammatory Cytokine Production by Macrophages and Acinar-to-Ductal Metaplasia of Pancreatic Cells.
Statins Inhibit Inflammatory Cytokine Production by Macrophages and Acinar-to-Ductal Metaplasia of Pancreatic Cells.
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他汀类药物抑制巨噬细胞的炎症细胞因子产生，胰腺细胞的腺泡到导管化生。
DOI：
10.1016/j.gastha.2022.04.012
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Eibl, Guido
中科院分区：
文献类型：
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作者：
Ako, Soichiro;Teper, Yaroslav;Ye, Linda;Sinnett-Smith, James;Hines, Oscar J;Rozengurt, Enrique;Eibl, Guido
动物数据显示，胰腺腺泡细胞中致癌Kras突变的存在导致腺泡-导管化生（ADM）、胰腺上皮内瘤变（PanIN）和胰腺导管腺癌（PDAC）。炎性巨噬细胞在ADM的形成和向PanIN的转化中起重要作用。流行病学上，他汀类药物与PDAC风险降低相关。我们研究了他汀类药物是否抑制巨噬细胞中炎性细胞因子的产生，以及这是否导致ADM形成减少。实时聚合酶链反应和酶联免疫吸附试验测定他汀类药物对2种巨噬细胞系中炎性细胞因子产生的疗效。观察巨噬细胞条件培养液对原代胰腺腺泡细胞ADM的影响。分析小鼠胰腺组织样品的巨噬细胞数量、细胞因子水平和肿瘤/发育不良面积。亲脂性他汀类药物可阻止脂多糖刺激的Raw 264.7和J774A.1细胞中炎性细胞因子的产生。他汀类药物的抑制作用是通过抑制甲羟戊酸和香叶基香叶基焦磷酸合成和破坏肌动蛋白细胞骨架介导的，但不是通过减少细胞内胆固醇。用亲脂性他汀类药物治疗巨噬细胞也阻断了原代胰腺腺泡细胞的ADM形成。此外，口服辛伐他汀与胰腺内巨噬细胞数量减少，胰腺中炎性细胞因子水平降低，以及小鼠ADM/PanIN形成减弱相关。我们的数据支持他汀类药物通过影响巨噬细胞和ADM形成来对抗早期PDAC发展的假设。他汀类药物对巨噬细胞的抑制作用可能与对转化胰腺上皮细胞的直接抑制作用协同作用，累积起来可能会减少早期PDAC的发生和进展。
Animal data show that the presence of an oncogenic Kras mutation in pancreatic acinar cells leads to acinar-to-ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and pancreatic ductal adenocarcinoma (PDAC). Inflammatory macrophages play an important role in the formation of ADMs and transition to PanINs. Epidemiologically, statins are associated with a reduced risk of PDAC. We investigated whether statins inhibit inflammatory cytokine production in macrophages and whether this leads to reduced ADM formation. The efficacy of statins on inflammatory cytokine production in 2 macrophage cell lines was measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of macrophage-conditioned medium on ADM in primary pancreatic acinar cells was investigated. Mouse pancreatic tissue samples were analyzed for macrophage numbers, cytokine levels, and neoplastic/dysplastic area. Lipophilic statins prevented inflammatory cytokine production in Raw264.7 and J774A.1 cells stimulated by lipopolysaccharide. The inhibitory effect of statins was mediated by inhibition of mevalonate and geranylgeranyl pyrophosphate synthesis and disruption of the actin cytoskeleton but not by a reduction in intracellular cholesterol. Treatment of macrophages with lipophilic statins also blocked ADM formation of primary pancreatic acinar cells. Furthermore, oral administration of simvastatin was associated with a reduction in the number of intrapancreatic macrophages, decreased inflammatory cytokine levels in the pancreas, and attenuated ADM/PanIN formation in mice. Our data support the hypothesis that statins oppose early PDAC development by their effects on macrophages and ADM formation. The inhibitory actions of statins on macrophages may collaborate with direct inhibitory effects on transformed pancreatic epithelial cells, which cumulatively may reduce early PDAC development and progression.