Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ target genes in hepatocytes.
Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ target genes in hepatocytes.
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DOI：
10.1016/j.jhep.2021.02.004
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发表时间：
2021-07
影响因子：
25.7
通讯作者：
Gao B
中科院分区：
文献类型：
--
作者：
He Y;Feng D;Hwang S;Mackowiak B;Wang X;Xiang X;Rodrigues RM;Fu Y;Ma J;Ren T;Ait-Ahmed Y;Xu M;Liangpunsakul S;Gao B
白细胞介素-20（IL-20）和IL-22属于IL-10家族。IL-10是一种有据可查的抗炎细胞因子，而IL-22以其上皮保护和抗菌功能而闻名，显示出对器官损伤的巨大治疗潜力;但IL-20的功能在很大程度上仍然未知。产生IL-20敲除（IL 20-/-）小鼠和野生型同窝出生小鼠，并注射伴刀豆球蛋白A（ConA）和肺炎克雷伯氏菌（K. P.）分别诱发急性肝炎和细菌感染。IL 20 −/−小鼠对急性肝炎具有抵抗力，选择性升高肝脏保护细胞因子IL-6水平，而不影响大多数其他细胞因子。IL-20对IL-6的这种选择性抑制是由于IL-20靶向肝细胞产生高水平的IL-6但产生有限数量的其他细胞因子。从机制上讲，IL-20上调NAD（P）H：醌氧化还原酶1（NQO 1）表达，随后促进转录因子IκB β的蛋白降解，导致IκB β依赖性基因II 6以及其他几种IκB β依赖性基因（包括脂质运载蛋白-2（Lcn 2））的选择性下调。鉴于IL-6和LCN 2在限制细菌感染中的重要作用，我们检查了IL-20对细菌感染的影响，发现IL-20 −/−小鼠对K. P.感染具有抗性，同时伴有肝脏IκB β依赖性抗菌基因的升高。此外，IL-20通过与IL-22 R1/IL-20 R2结合激活ERK/p38 MAPK/NRF 2信号通路而上调肝NQO 1。最后，在急性酒精性肝炎患者中，肝脏IL 1 B、IL 20和IκB β靶基因升高并且相互关联。IL-20选择性地抑制肝脏IL-6的产生，而不是发挥IL-10样的广泛抗炎特性，并且与IL-22相比，通过加重急性肝炎和细菌感染而具有相反的功能。因此，抗IL-20治疗可能有助于控制急性肝炎和细菌感染。免疫细胞来源的IL-20通过与IL-22 R1/IL-20 R2结合激活ERK/NRF 2和p38/NRF 2信号通路诱导肝细胞中NQO 1表达。升高的NQO 1促进肝细胞中IκB β降解，随后下调IκB β靶向的肝保护和抗菌基因（例如IL 6和Lcn 2），从而加速急性肝炎和细菌感染。总的来说，IL-20通过下调肝细胞中IκB β靶基因而加重急性肝炎和细菌感染。
Interleukin-20 (IL-20) and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well-known for its epithelial protection and anti-bacterial function, showing great therapeutic potential for organ damage; but the function of IL-20 remains largely unknown. IL-20 knockout (Il20−/−) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively. Il20−/− mice were resistant to acute hepatitis with selective elevation of the hepatoprotective cytokine IL-6 levels without affecting most other cytokines. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting-hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given an important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20−/− mice were resistant to K.P. infection accompanied with an elevation of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by activating ERK/p38MAPK/NRF2 signaling pathways via the binding of IL-22R1/IL-20R2. Finally, hepatic IL1B, IL20, and IκBζ target genes are elevated and correlated each other in patients with acute alcoholic hepatitis. IL-20 selectively inhibits hepatic IL-6 production rather than exerts an IL-10 like broad anti-inflammatory properties and has opposing functions compared to IL-22 by aggravating acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy may have benefits to control acute hepatitis and bacterial infection. Immune cell-derived IL-20 induces NQO1 expression in hepatocytes by activating ERK/NRF2 and p38/NRF2 signaling pathway via the binding of IL-22R1/IL-20R2. The elevated NQO1 promotes IκBζ degradation in hepatocytes and subsequently downregulates IκBζ-target hepatoprotective and anti-bacterial genes (e.g. Il6 and Lcn2), thereby accelerating acute hepatitis and bacterial infection. Collectively, IL-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ-target genes in hepatocytes.
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