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首页> 外文期刊>Clinical and Experimental Immunology: An Official Journal of the British Society for Immunology >Regulatory role of PI3K-protein kinase B on the release of interleukin-1 beta in peritoneal macrophages from the ascites of cirrhotic patients
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Regulatory role of PI3K-protein kinase B on the release of interleukin-1 beta in peritoneal macrophages from the ascites of cirrhotic patients

机译：PI3K蛋白激酶B对肝硬化腹水患者腹膜巨噬细胞白细胞介素1β释放的调节作用

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Great effort has been paid to identify novel targets for pharmaceutical intervention to control inflammation associated with different diseases. We have studied the effect of signalling inhibitors in the secretion of the proinflammatory and profibrogenic cytokine interleukin (IL)-1 in monocyte-derived macrophages (M-DM) obtained from the ascites of cirrhotic patients and compared with those obtained from the blood of healthy donors. Peritoneal M-DM were isolated from non-infected ascites of cirrhotic patients and stimulated in vitro with lipopolysaccharide (LPS) and heat-killed Candida albicans in the presence or absence of inhibitors for c-Jun N-terminal kinase (JNK), mitogen-activated protein kinase kinase 1 (MEK1), p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). The IL1B and CASP1 gene expression were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression of IL-1 and caspase-1 were determined by Western blot. IL-1 was also assayed by enzyme-linked immunosorbent assay (ELISA) in cell culture supernatants. Results revealed that MEK1 and JNK inhibition significantly reduced the basal and stimulated IL-1 secretion, while the p38 MAPK inhibitor had no effect on IL-1 levels. On the contrary, inhibition of PI3K increased the secretion of IL-1 from stimulated M-DM. The activating effect of PI3K inhibitor on IL-1 release was mediated mainly by the enhancement of the intracellular IL-1 and caspase-1 content release to the extracellular medium and not by increasing the corresponding mRNA and protein expression levels. These data point towards the role of MEK1 and JNK inhibitors, in contrast to the PI3K-protein kinase B inhibitors, as potential therapeutic tools for pharmaceutical intervention to diminish hepatic damage by reducing the inflammatory response mediated by IL-1 associated with liver failure.
机译：已经付出巨大的努力来确定药物干预的新靶标，以控制与不同疾病相关的炎症。我们已经研究了信号抑制剂在肝硬化患者腹水中获得的单核细胞衍生巨噬细胞（M-DM）中促炎和纤维原性细胞因子白介素（IL）-1分泌中的作用，并与健康人血液中的抑制剂进行了比较捐助者。从未感染的肝硬化患者腹水中分离出腹膜M-DM，并在存在或不存在c-Jun N端激酶（JNK）抑制剂，有丝分裂原-抑制剂的条件下，用脂多糖（LPS）和热杀死的白色念珠菌体外刺激。活化蛋白激酶激酶1（MEK1），p38丝裂原活化蛋白激酶（MAPK）和磷脂酰肌醇-4,5-双磷酸3激酶（PI3K）。通过定量逆转录-聚合酶链反应（qRT-PCR）评估IL1B和CASP1基因表达。通过蛋白质印迹法测定IL-1和caspase-1的表达。还通过酶联免疫吸附测定（ELISA）在细胞培养上清液中测定IL-1。结果表明，MEK1和JNK的抑制作用显着降低了基础和刺激的IL-1分泌，而p38 MAPK抑制剂对IL-1水平没有影响。相反，抑制PI3K增加了受刺激的M-DM中IL-1的分泌。 PI3K抑制剂对IL-1释放的激活作用主要是通过增强细胞内IL-1和caspase-1含量释放到细胞外介质来实现的，而不是通过增加相应的mRNA和蛋白质表达水平来介导的。这些数据表明，与PI3K蛋白激酶B抑制剂相反，MEK1和JNK抑制剂的作用是作为药物干预的潜在治疗工具，可通过减少与肝衰竭相关的IL-1介导的炎症反应来减轻肝损伤。

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