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Prostaglandin E2 and an EP4 receptor agonist inhibit LPS-Induced monocyte chemotactic protein 5 production and secretion in mouse cardiac fibroblasts via Akt and NF-κB signaling.
ProstaglandIns & Other Lipid Mediators ( IF 2.9 ) Pub Date : 2019-06-20 , DOI: 10.1016/j.prostaglandins.2019.106349 Timothy D Bryson 1 , Jacob Ross 2 , Edward Peterson 3 , Pamela Harding 1
ProstaglandIns & Other Lipid Mediators ( IF 2.9 ) Pub Date : 2019-06-20 , DOI: 10.1016/j.prostaglandins.2019.106349 Timothy D Bryson 1 , Jacob Ross 2 , Edward Peterson 3 , Pamela Harding 1
Affiliation
BACKGROUND
Prostaglandin E2 (PGE2) signals through 4 separate G-protein coupled receptor sub-types to elicit a variety of physiologic and pathophysiological effects. We have previously reported that mice lacking the EP4 receptor in the cardiomyocytes develop heart failure with a phenotype of dilated cardiomyopathy. Also, these mice have increased levels of chemokines, like MCP-5, in their left ventricles. We have recently reported that overexpression of the EP4 receptor could improve cardiac function in the myocardial infarction model. Furthermore, we showed that overexpression of EP4 had an anti-inflammatory effect in the whole left ventricle. It has also been shown that PGE2 can antagonize lipopolysaccharide-induced secretion of chemokines/cytokines in various cell types. We therefore hypothesized that PGE2 inhibits lipopolysaccharide (LPS)-induced MCP-5 secretion in adult mouse cardiac fibroblasts via its EP4 receptor.
METHODS AND RESULTS
Our hypothesis was tested using isolated mouse adult ventricular fibroblasts (AVF) treated with LPS. Pre-treatment of the cells with PGE2 and the EP4 agonist CAY10598 resulted in reductions of the pro-inflammatory response induced by LPS. Specifically, we observed reductions in MCP-5 secretion. Western blot analysis showed reductions in phosphorylated Akt and IκBα indicating reduced NF-κB activation. The anti-inflammatory effects of PGE2 and EP4 agonist signaling appeared to be independent of cAMP, p-44/42, or p38 pathways.
CONCLUSION
Exogenous treatment of PGE2 and the EP4 receptor agonist blocked the pro-inflammatory actions of LPS. Mechanistically, this was mediated via reduced Akt phosphorylation and inhibition of NF-κB.
中文翻译：
前列腺素E2和EP4受体激动剂通过Akt和NF-κB信号传导抑制LPS诱导的小鼠成纤维细胞单核细胞趋化蛋白5的产生和分泌。
背景技术前列腺素E2（PGE2）通过4种单独的G蛋白偶联受体亚型发出信号，以引起多种生理和病理生理作用。我们以前曾报道过，心肌细胞中缺乏EP4受体的小鼠会出现心力衰竭，并表现为扩张型心肌病的表型。而且，这些小鼠的左心室中的趋化因子（如MCP-5）水平升高。最近，我们报道了EP4受体的过度表达可以改善心肌梗塞模型的心脏功能。此外，我们表明，EP4的过表达在整个左心室具有抗炎作用。还已经显示，PGE 2可以拮抗脂多糖诱导的多种细胞类型中趋化因子/细胞因子的分泌。因此，我们假设PGE2通过其EP4受体抑制成年小鼠心脏成纤维细胞中脂多糖（LPS）诱导的MCP-5分泌。方法和结果我们的假设是使用经LPS治疗的分离的小鼠成年心室成纤维细胞（AVF）进行检验的。用PGE2和EP4激动剂CAY10598预处理细胞可降低LPS诱导的促炎反应。具体而言，我们观察到MCP-5分泌减少。蛋白质印迹分析显示磷酸化的Akt和IκBα减少，表明NF-κB激活减少。PGE2和EP4激动剂信号传导的抗炎作用似乎独立于cAMP，p-44 / 42或p38途径。结论PGE2和EP4受体激动剂的外源性治疗阻断了LPS的促炎作用。机械上，
更新日期：2019-11-01
中文翻译：
前列腺素E2和EP4受体激动剂通过Akt和NF-κB信号传导抑制LPS诱导的小鼠成纤维细胞单核细胞趋化蛋白5的产生和分泌。
背景技术前列腺素E2（PGE2）通过4种单独的G蛋白偶联受体亚型发出信号，以引起多种生理和病理生理作用。我们以前曾报道过，心肌细胞中缺乏EP4受体的小鼠会出现心力衰竭，并表现为扩张型心肌病的表型。而且，这些小鼠的左心室中的趋化因子（如MCP-5）水平升高。最近，我们报道了EP4受体的过度表达可以改善心肌梗塞模型的心脏功能。此外，我们表明，EP4的过表达在整个左心室具有抗炎作用。还已经显示，PGE 2可以拮抗脂多糖诱导的多种细胞类型中趋化因子/细胞因子的分泌。因此，我们假设PGE2通过其EP4受体抑制成年小鼠心脏成纤维细胞中脂多糖（LPS）诱导的MCP-5分泌。方法和结果我们的假设是使用经LPS治疗的分离的小鼠成年心室成纤维细胞（AVF）进行检验的。用PGE2和EP4激动剂CAY10598预处理细胞可降低LPS诱导的促炎反应。具体而言，我们观察到MCP-5分泌减少。蛋白质印迹分析显示磷酸化的Akt和IκBα减少，表明NF-κB激活减少。PGE2和EP4激动剂信号传导的抗炎作用似乎独立于cAMP，p-44 / 42或p38途径。结论PGE2和EP4受体激动剂的外源性治疗阻断了LPS的促炎作用。机械上，
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