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.
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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

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Figure 7

Restoring the IFN-γ/pSTAT1/IRF1 pathway increases liver damage.

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Restoring the IFN-γ/pSTAT1/IRF1 pathway increases liver damage. (A) West...
(A) Western blot for pSTAT1 and total STAT1 2 hours after treatment with ConA. One set of JunbΔli* mice received 200 ng recombinant IFN-γ 1 hour after ConA treatment (n = 3). (B) Serum ALT levels 8 hours after mock or ConA injection. Left panel: control and JunbΔli* mice received 200 ng recombinant IFN-γ 1 hour after mock treatment (n = 3). Right panel: all mice were treated with ConA, and a subset of control and JunbΔli* mice received 200 ng recombinant IFN-γ 1 hour later (n = 8 control, n = 5 JunbΔli*, 5 control plus IFN-γ, and JunbΔli* plus IFN-γ; *P < 0.05). (C) qRT-PCR for stress-related genes in the liver 8 hours after ConA treatment. A subset of control and JunbΔli* mice received 200 ng recombinant IFN-γ 1 hour later (n = 4; *P < 0.05, significantly different from ConA-treated control mice). (D) Mice were treated with adenovirus 4 days prior to ConA treatment, as indicated. Western blot for IRF1 and GFP. Vinculin is included to control for equal loading. ALT measurement 8 hours after ConA treatment (n = 10 control plus Ad-GFP, 3 JunbΔli* plus Ad-GFP, 6 JunbΔli* plus Ad-IRF1 mice; *P < 0.05). (E) Illustration of the function of JUNB in modulating acute liver injury. During acute hepatitis, JUNB regulates Ifng expression in NK and NKT cells and Il2 in T cells. IL-2 increases NK and NKT cell activation. NK cell– and NKT cell–derived IFN-γ induces phosphorylation of STAT1 and the expression of STAT1 targets in hepatocytes, leading to cell death.