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

Abstract Background & Aims 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. Methods 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. Results 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. Conclusions 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.