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 1

JUNB expression in immune cells from livers of patients with hepatitis.

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JUNB expression in immune cells from livers of patients with hepatitis. ...
(A) Liver sections from healthy patients or patients with hepatitis were stained with H&E (scale bar: 50 μm) or with an antibody against JUNB (brown). Insets show representative inflamed areas. Black arrowheads indicate JUNB-positive cells (n = 5). Representative areas are shown. (B) Quantification of JUNB-positive cells in liver sections from healthy patients and those with hepatitis (n = 5, *P < 0.05). (C) Hepatitis samples were stained for JUNB (brown) and with a marker for immune cells (CD45), monocytes/macrophages (CD68), T cells (CD3), or NK and NKT cells (CD56) (red). JUNB-single positive cells are indicated with black arrowheads and double-positive cells are indicated with pink arrowheads. (D) Liver sections from wild type-mice treated or untreated with ConA for 2 hours and from ConA-treated JunbΔli* mice were stained for JUNB (brown). Black arrowheads indicate JUNB-positive cells. Immune-fluorescense costaining of livers from ConA-treated mice for JunB (red) and CD45 (white). White arrows indicate double-positive cells. Scale bar: 20 μm. One representative experiment is shown (n > 5).