Essential role of STAT-3 dependent NF-κB activation on IL-6-mediated downregulation of hepatic transporters
Essential role of STAT-3 dependent NF-κB activation on IL-6-mediated downregulation of hepatic transporters
复制标题
STAT-3依赖的NF-κB活化在IL-6介导的肝转运蛋白下调中的重要作用
DOI：
10.1016/j.ejps.2019.105151
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发表时间：
2020-02-15
影响因子：
4.6
通讯作者：
Piquette-Miller, Micheline
中科院分区：
文献类型：
--
作者：
Abualsunun, Walaa A.;Sahin, Cigdem;Piquette-Miller, Micheline
IL-6显著降低许多肝转运蛋白的表达。我们先前证明IL-6介导的转运蛋白下调通过STAT 3发生，部分参与PXR。然而，虽然IL-6介导的STAT 3诱导迅速发生，但直到治疗后6小时才观察到转运蛋白表达的抑制。这种时间上的不匹配表明，IL-6在6小时后转运蛋白的下调可能需要STAT 3下游的额外信号传导。由于NF-κ B参与内毒素介导的转运蛋白下调，我们假设NF-κ B可能类似地参与IL-6后转运蛋白表达的抑制。我们的目的是研究IL-6介导的转运蛋白表达的变化是否通过STAT 3依赖的NF-κ B激活发生，以及PXR是否参与其中。在接受单次剂量的IL-6或盐水之前30分钟，将NF-κ B抑制剂PHA 408或媒介物预给药于PXR无效（-/-）或野生型（+/+）小鼠。6小时后将小鼠安乐死，并使用qRT-PCR分析转运蛋白表达。在PXR（+/+）和PXR（-/-）小鼠中，IL-6均使Abcbla、Abcb 1b、Abcc 3、Abcg 2和Cyp 3a 11下调，而Abcb 11、Abcc 2、Slc 10a 1和Slco 2b 1的下调仅在PXR（+/+）小鼠中显著。PHA 408预处理完全抑制PXR（+/+）中的NF-κ B活化，但仅部分抑制PXR（-/-）中的NF-κ B活化。抑制NF-κ B可减弱PXR（+/+）小鼠中IL-6介导的转运蛋白变化。瞬时转染试验未检测到PHA 408对人或小鼠PXR的显著激活。我们的研究结果表明，IL-6通过协同STAT 3/NF-κ B激活显著下调肝脏中的许多ABC和SLC转运蛋白。由于药物转运蛋白在许多临床相关药物的药代动力学中发挥着不可或缺的作用，因此了解炎症期间转运蛋白调节所涉及的信号通路将有助于更好地了解药物与疾病的相互作用。
IL-6 markedly decreases the expression of numerous hepatic transporters. We previously demonstrated that IL-6-mediated downregulation of transporters occurs through STAT3, with partial involvement of PXR. However, while IL-6-mediated induction of STAT3 occurs rapidly, repression of transporter expression is not observed until 6 h post-treatment. This temporal mismatch suggested that the downregulation of transporters following IL-6 at 6 h might require additional signaling downstream of STAT3. Since NF-kappa B has been implicated in endotoxin-mediated downregulation of transporters, we hypothesized that NF-kappa B may be similarly involved in suppressing transporter expression following IL-6. Our objective was to investigate whether IL-6-mediated changes in transporter expression occur through STAT3-dependent NF-kappa B activation, and whether PXR is involved. PXR null (-/-) or wild type (+/+) mice were pre-dosed with the NF-kappa B inhibitor PHA408 or vehicle 30 min prior to receiving a single dose of IL-6 or saline. Mice were euthanized after 6 h and transporter expression was analyzed using qRT-PCR. IL-6 imposed downregulation of Abcbla, Abcb1b, Abcc3, Abcg2 and Cyp3a11 in both PXR (+/+) and PXR (-/-) mice, while downregulation of Abcb11, Abcc2, Slc10a1, and Slco2b1 was only significant in PXR (+/+) mice. PHA408 pretreatment fully inhibited NF-kappa B activation in PXR (+/+) but only partially inhibited NF-kappa B in PXR (-/-). Inhibition of NF-kappa B attenuated IL-6-mediated changes in transporters in PXR (+/+) mice. Transient transfection assays did not detect significant activation of human or mouse PXR by PHA408. Our findings suggest that IL-6 imposes significant downregulation of numerous ABC and SLC transporters in the liver via collaborative STAT3/NF-kappa B activation. Since drug transporters play an integral role in the pharmacokinetics of numerous clinically relevant drugs, understanding the signaling pathways involved in transporter regulation during inflammation will contribute to a better understanding of drug-disease interactions.