JUNB/AP-1 controls IFN-γ during inflammatory liver disease
Martin K. Thomsen, Latifa Bakiri, Sebastian C. Hasenfuss, Rainer Hamacher, Lola Martinez, Erwin F. Wagner
Martin K. Thomsen, Latifa Bakiri, Sebastian C. Hasenfuss, Rainer Hamacher, Lola Martinez, Erwin F. Wagner
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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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