IL-6 通过 JAK/PI3K/Akt/CREB 信号通路调节肝细胞中 Mcl-1L 的表达：在肝再生过程中发挥抗细胞凋亡作用的意义。
IL-6 regulates Mcl-1L expression through the JAK/PI3K/Akt/CREB signaling pathway in hepatocytes: implication of an anti-apoptotic role during liver regeneration.
机构信息
Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
出版信息
PLoS One. 2013 Jun 25;8(6):e66268. doi: 10.1371/journal.pone.0066268. Print 2013.
AIMS
To investigate the role and the regulation of the long variant of myeloid cell leukemia-1 protein (Mcl-1L) during liver regeneration.
BACKGROUND
Liver regeneration is an important phenomenon after liver injury. The rat partial hepatectomy (PH) model was used to characterize liver regeneration and Mcl-1L expression after PH.
METHODS
Male Wistar rats were subjected to 70% PH. The expression of mcl-1L mRNA was determined by quantitative RT-PCR, and protein levels were analyzed by Western blot analysis and immunohistochemistry during liver regeneration. Functional evaluations of Mcl-1L were tested using chemical inhibition (flavopiridol), genetic inhibition (siRNA) of Mcl-1L production, and by assaying for annexin V levels and DNA ladder formation. Serum IL-6 levels were determined by enzyme immunoassays; signal transduction of IL-6-regulated Mcl-1L expression was verified by chemical inhibitors and decoy double-stranded oligodeoxynucleotides.
RESULTS
High levels of Mcl-1L were observed in remnant tissue at 4 h after PH. Administration of flavopiridol decreased Mcl-1L accumulation and also inhibited liver regeneration. IL-6 administration promoted the accumulation of Mcl-1L in rat hepatocytes, an effect that was impaired by siRNA treatments that reduced Mcl-1L production. Chemical inhibition and decoy oligonucleotide competition demonstrated that IL-6-induced Mcl-1L production required signaling mediated by JAK kinase, phosphoinositide 3-kinase (PI3K), and cAMP response-element-binding (CREB) proteins.
CONCLUSION
Mcl-1L is an anti-apoptotic protein induced during liver regeneration after PH in rats. The expression of Mcl-1L is induced by IL-6 through the JAK/PI3K/Akt/CREB signaling pathway. Chemotherapy drugs that depend on Mcl-1L- or IL-6-related signaling should be considered carefully before use in patients undergoing hepatectomy for malignant tumor resection.
目的
研究髓样细胞白血病-1 蛋白（Mcl-1L）长变体在肝再生过程中的作用和调节机制。
背景
肝再生是肝损伤后重要的现象。我们使用大鼠部分肝切除术（PH）模型来描述 PH 后肝再生和 Mcl-1L 表达的情况。
方法
雄性 Wistar 大鼠接受 70% PH。通过定量 RT-PCR 测定 mcl-1L mRNA 的表达，通过 Western blot 分析和免疫组化检测在肝再生过程中蛋白水平。使用化学抑制（flavopiridol）、Mcl-1L 产生的基因抑制（siRNA）以及检测 Annexin V 水平和 DNA 梯形成来测试 Mcl-1L 的功能。通过酶免疫测定法测定血清 IL-6 水平；通过化学抑制剂和诱饵双链寡脱氧核苷酸验证 IL-6 调节 Mcl-1L 表达的信号转导。
结果
PH 后 4 小时，残肝组织中观察到高水平的 Mcl-1L。给予 flavopiridol 可减少 Mcl-1L 积累并抑制肝再生。IL-6 给药促进了大鼠肝细胞中 Mcl-1L 的积累，而降低 Mcl-1L 产生的 siRNA 处理则削弱了这一作用。化学抑制和诱饵寡核苷酸竞争表明，IL-6 诱导的 Mcl-1L 产生需要 JAK 激酶、磷酸肌醇 3-激酶（PI3K）和 cAMP 反应元件结合（CREB）蛋白介导的信号转导。
结论
Mcl-1L 是大鼠 PH 后肝再生过程中的一种抗凋亡蛋白。Mcl-1L 的表达通过 JAK/PI3K/Akt/CREB 信号通路被 IL-6 诱导。在因恶性肿瘤切除而行肝切除术的患者中使用依赖于 Mcl-1L 或 IL-6 相关信号的化疗药物时应慎重考虑。
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