Protective Effects of Oridonin on Acute Liver Injury via Impeding Posttranslational Modifications of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) in the Toll-Like Receptor 4 (TLR4) Signaling Pathway
Protective Effects of Oridonin on Acute Liver Injury via Impeding Posttranslational Modifications of Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) in the Toll-Like Receptor 4 (TLR4) Signaling Pathway
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冬凌草甲素通过阻碍 Toll 样受体 4 (TLR4) 信号通路中白细胞介素 1 受体相关激酶 4 (IRAK4) 的翻译后修饰对急性肝损伤的保护作用
DOI：
10.1155/2019/7634761
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发表时间：
2019-09
影响因子：
4.6
通讯作者：
Yu-gang Wang
中科院分区：
文献类型：
--
作者：
Min Shi;Yilin Deng;Heguo Yu;Ling Xu;Cuicui Shi;Jiong Chen;Guangming Li;Yiqi Du;Yu-gang Wang
目的近年来的研究表明，炎症相关疾病的发生与翻译后修饰（PTMs）有关，包括磷酸化和乙酰化。我们前期研究发现了一种新的乙酰转移酶抑制剂冬凌草甲素，它对急性肝损伤（ALI）有保护作用。本研究进一步探讨其对D-氨基半乳糖（D-Gal）联合脂多糖（LPS）诱导的小鼠急性肺损伤的保护作用机制。方法腹腔注射LPS（40 μg/只）/D-Gal（5 mg/只），实验组腹腔注射冬凌草甲素（0.2mg/只）。为了阐明冬凌草甲素的保护机制，我们收集了肝脏标本，并使用RNA测序（RNA-Seq）分析。我们重点研究了LPS/D-Gal上调和冬凌草甲素预处理后下调的基因。通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）途径分析检测的下调基因进一步通过实时聚合酶链反应（PCR）和western blot进行验证。结果GO分析显示，经冬凌草甲素预处理后下调的基因极其集中在免疫反应、趋化反应和炎症反应中。Real-time PCR证实LPS/D-Gal诱导后这些基因的表达上调，冬凌草甲素处理后这些基因的表达下调，这与RNA-Seq结果一致。KEGG通路分析显示Toll样受体（TLR）4信号级联中存在显著富集的下调基因。结果表明，冬凌草甲素能显著抑制TLR 4信号级联反应中细胞外信号调节激酶（ERK）、P38和IκB的磷酸化水平。此外，LPS/D-Gal刺激触发TLR 4信号通路中相关基因位点的翻译后修饰，包括IL-1受体相关激酶4（IRAK 4 T345/S346）的磷酸化和IRAK 4（K34）的乙酰化。然而，经冬凌草甲素处理后，LPS/D-Gal刺激的IRAK 4表达的修饰模式被连续减弱。结论冬凌草甲素对LPS/D-Gal诱导的ALI具有保护作用，其机制可能与抑制IRAK 4的T345/S346磷酸化和K34乙酰化有关。
Objective Recent researches have demonstrated that inflammation-related diseases are effectively regulated by posttranslational modifications (PTMs) including phosphorylation and acetylation. Our previous study found a new acetyltransferase inhibitor, oridonin, which had a protective effect on acute liver injury (ALI). In the present study, we further investigated its protective mechanism against D-galactosamine (D-Gal) combined with lipopolysaccharide- (LPS-) induced ALI in mice. Methods Intraperitoneal injections of LPS (40 μg/mouse)/D-Gal (5 mg/mouse) were given to the mice, and the experimental group was pretreated with intraperitoneal injection of oridonin (0.2 mg/mouse). To elucidate the protective mechanism of oridonin, we collected liver specimens and used RNA-sequencing (RNA-Seq) analysis. We focused on the genes that were upregulated by LPS/D-Gal and downregulated after pretreatment with oridonin. The downregulated genes examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were further verified by real-time polymerase chain reaction (PCR) and western blot. Results GO analysis showed that genes that were downregulated after pretreatment with oridonin were extremely concentrated in immune response, chemotaxis, and inflammatory response. Real-time PCR confirmed that the expression of these genes was upregulated by LPS/D-Gal induction and reduced after treatment with oridonin, which was consistent with RNA-Seq results. KEGG pathway analysis showed a significantly enriched downregulated gene that was present in the Toll-like receptor (TLR) 4 signaling cascade. Our results manifested that phosphorylation levels of upstream signaling molecules in the TLR4 signaling cascade, including extracellular signal-regulated kinase (ERK), P38, and IκB, were significantly inhibited by oridonin. Furthermore, LPS/D-Gal stimulation triggered posttranslational modifications of related gene loci in the TLR4 signaling pathway, including phosphorylation of IL-1 receptor-associated kinase 4 (IRAK4 T345/S346) and acetylation of IRAK4 (K34). However, after treatment with oridonin, the modification pattern of IRAK4 expression stimulated by LPS/D-Gal was suggestively attenuated. Conclusion Our study revealed that the protective effects of oridonin on LPS/D-Gal-induced ALI mediated by inhibition of the PTMs of IRAK4, including phosphorylation of T345/S346 and acetylation of K34.
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