Interleukin-20 exacerbates acute hepatitis and bacterial infection by downregulating IκBζ target genes in hepatocytes

• Published in: Journal of hepatology 2021-07, Vol.75 (1), p.163-176
• Main Authors: He, Yong, Feng, Dechun, Hwang, Seonghwan, Mackowiak, Bryan, Wang, Xiaolin, Xiang, Xiaogang, Rodrigues, Robim M., Fu, Yaojie, Ma, Jing, Ren, Tianyi, Ait-Ahmed, Yeni, Xu, Mingjiang, Liangpunsakul, Suthat, Gao, Bin
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Anti-inflammatory agents; Bacteria; Bacterial infections; Bacterial Infections - drug therapy; Bacterial Infections - immunology; Bacterial Infections - metabolism; Biodegradation; Concanavalin A; Cytokines; Drug Discovery; Gene Expression Regulation - drug effects; Hepatitis; Hepatitis - drug therapy; Hepatitis - immunology; Hepatitis - metabolism; Hepatitis, Alcoholic - immunology; Hepatitis, Alcoholic - metabolism; Hepatocytes; Humans; IL-10; IL-1β; IL-22; Infections; Inflammation; Interleukin 1; Interleukin 10; Interleukin 20; Interleukin 22; Interleukin 6; Interleukin-1beta - metabolism; Interleukins - metabolism; Klebsiella pneumonia; Lipocalin; liver; Liver - metabolism; Liver diseases; Mice; Mice, Knockout; NAD; NAD(P)H Dehydrogenase (Quinone) - metabolism; NQO1; Patients; Proteolysis; Quinone oxidoreductase; Up-Regulation
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2021.02.004

Interleukin (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 epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown. Il20 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 and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. 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 the 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 and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis. IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection. Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease. [Display omitted] •IL-20 exacerbates acute hepatitis and bacterial infection.•IL-20 selectively inhibits IL-6 and LCN2 express