JUNB/AP-1 controls IFN-γ during inflammatory liver disease
Martin K. Thomsen, … , Lola Martinez, Erwin F. Wagner
Martin K. Thomsen, … , Lola Martinez, Erwin F. Wagner
Published November 8, 2013
Citation Information: J Clin Invest. 2013;123(12):5258-5268. https://doi.org/10.1172/JCI70405.
View: Text | PDF
Research Article Hepatology

JUNB/AP-1 controls IFN-γ during inflammatory liver disease

Abstract

Understanding the molecular pathogenesis of inflammatory liver disease is essential to design efficient therapeutic approaches. In hepatocytes, the dimeric transcription factor c-JUN/AP-1 is a major mediator of cell survival during hepatitis, although functions for other JUN proteins in liver disease are less defined. Here, we found that JUNB was specifically expressed in human and murine immune cells during acute liver injury. We analyzed the molecular function of JUNB in experimental models of hepatitis, including administration of concanavalin A (ConA) or α-galactosyl-ceramide, which induce liver inflammation and injury. Mice specifically lacking JUNB in hepatocytes displayed a mild increase in ConA-induced liver damage. However, targeted deletion of Junb in immune cells and hepatocytes protected against hepatitis in experimental models that involved NK/NKT cells. The absence of JUNB in immune cells decreased IFN-γ expression and secretion from NK and NKT cells, leading to reduced STAT1 pathway activation. Systemic IFN-γ treatment or adenovirus-based IRF1 delivery to Junb-deficient mice restored hepatotoxicity, and we demonstrate that Ifng is a direct transcriptional target of JUNB. These findings demonstrate that JUNB/AP-1 promotes cell death during acute hepatitis by regulating IFN-γ production in NK and NKT cells and thus functionally antagonizes the hepatoprotective function of c-JUN/AP-1 in hepatocytes.

Authors

Martin K. Thomsen, Latifa Bakiri, Sebastian C. Hasenfuss, Rainer Hamacher, Lola Martinez, Erwin F. Wagner

×

Figure 6

JUNB regulates IFN-γ in NK and NKT cells.

Options: View larger image (or click on image) Download as PowerPoint
JUNB regulates IFN-γ in NK and NKT cells. Control and JunbΔli* mice were...
Control and JunbΔli* mice were treated with (A) ConA or (B) αGalCer (n = 5) or not treated (n = 3) for 2 hours, and T (CD3+, NK1.1–), NK (CD3–, NK1.1+), and NKT (CD3+, NK1.1+) cells were isolated from spleens by flow cytometry and analyzed by qRT-PCR for gene expression. *P < 0.05. (C) The human/mouse Ifng promoter. The position of the putative AP-1 binding TRE element included in the ChIP amplicon is indicated relative to the transcription start site. (D) Quantitative ChIP analysis of the Ifng, Il2, and S16 promoters in control and JunbΔli* livers after treatment with ConA using an antibody to JUNB or IgG. Input chromatin samples were run in parallel, and percentage of amplification relative to input for each antibody was quantified by qPCR and plotted (n = 3; *P < 0.05). Human YT NK cells were treated with P/I for 2 hours. (E) qRT-PCR expression of JUNB, IFNG, and IL2 (n = 3; *P < 0.05). (F) Western blot analysis of JUNB. (G) Representative agarose gel picture of end point PCR amplification for a ChIP of the IFNG promoter using an antibody to JUNB or IgG in YT cells. Input chromatin sample was run in parallel. (H) Quantitative ChIP analysis of the IFNG, IL2, and GAPDH promoters in untreated or P/I-stimulated YT cells using an antibody to JUNB or IgG. Input chromatin samples were run in parallel, and the percentage of amplification relative to input for each antibody was quantified by qPCR and plotted (n = 3; *P < 0.05).