Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways.
Penicillinase-resistant antibiotics induce non-immune-mediated cholestasis through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways.
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DOI：
10.1038/s41598-017-01171-y
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发表时间：
2017-05-12
影响因子：
4.6
通讯作者：
Guguen-Guillouzo C
中科院分区：
文献类型：
--
作者：
Burban A;Sharanek A;Hüe R;Gay M;Routier S;Guillouzo A;Guguen-Guillouzo C
青霉素酶耐药抗生素（PRA），特别是高度处方的氟氯西林，通过在很大程度上尚未阐明的机制引起频繁的肝损伤。我们首先发现，在不存在免疫反应的情况下，氟氯西林（不依赖于细胞毒性）可在人肝细胞中表现出胆汁淤积作用，其典型表现为与Rho激酶信号通路受损相关的胆小管扩张和胆汁酸流出减少。然后，我们分析了氟氯西林诱导的胆汁淤积中所涉及的连续分子事件。使用siRNA和特异性抑制剂KRIBB 3证明了HSP 27通过抑制Rho激酶活性的关键作用。HSP 27的激活依赖于PKC/P38通路，并导致下游的PI 3 K/AKT通路的激活。其他PRA诱导类似的胆汁淤积作用，而非PRA无效。我们的研究结果表明，PRA可以通过激活与PKC/P38和PI 3 K/AKT信号通路相关的HSP 27诱导人肝细胞的胆汁淤积特征，从而支持在临床上它们可以引起非免疫介导的胆汁淤积的结论，这并不限于具有某些遗传决定因素的患者。
The penicillinase-resistant antibiotics (PRAs), especially the highly prescribed flucloxacillin, caused frequent liver injury via mechanisms that remain largely non-elucidated. We first showed that flucloxacillin, independently of cytotoxicity, could exhibit cholestatic effects in human hepatocytes in the absence of an immune reaction, that were typified by dilatation of bile canaliculi associated with impairment of the Rho-kinase signaling pathway and reduced bile acid efflux. Then, we analyzed the sequential molecular events involved in flucloxacillin-induced cholestasis. A crucial role of HSP27 by inhibiting Rho-kinase activity was demonstrated using siRNA and the specific inhibitor KRIBB3. HSP27 activation was dependent on the PKC/P38 pathway, and led downstream to activation of the PI3K/AKT pathway. Other PRAs induced similar cholestatic effects while non PRAs were ineffective. Our results demonstrate that PRAs can induce cholestatic features in human hepatocytes through HSP27 activation associated with PKC/P38 and PI3K/AKT signaling pathways and consequently support the conclusion that in clinic they can cause a non-immune-mediated cholestasis that is not restricted to patients possessing certain genetic determinants.