IFN-γ/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1

Abstract

We have previously shown that IFN-gamma/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-gamma/STAT1 also plays a crucial role in leukocyte infiltration into the liver in T cell hepatitis. After injection of ConA, leukocytes were significantly infiltrated into the liver, which was suppressed in IFN-gamma(-/-) and STAT1(-/-) mice. Disruption of the IFN regulatory factor-1 (IRF-1) gene, a downstream target of IFN-gamma/STAT1, abolished ConA-induced liver injury and suppressed leukocyte infiltration into the liver. Additionally, ConA injection induced expression of a wide variety of chemokines and adhesion molecules in the liver. Among them, expression of ICAM-1, VCAM-1, monokine induced by IFN-gamma (Mig), CC chemokine ligand-20, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IFN-inducible T cell-alpha chemoattractant (I-TAC), and IFN-inducible protein-10 (IP-10) was markedly attenuated in IFN-gamma(-/-), STAT1(-/-), and IRF-1(-/-) mice. In primary mouse hepatocytes, Kupffer cells, and endothelial cells, in vitro treatment with IFN-gamma activated STAT1, STAT3, and IRF-1, and induced expression of VCAM-1, ICAM-1, Mig, ENA-78, I-TAC, and IP-10 mRNA. Induction of these chemokines and adhesion molecules was markedly diminished in STAT1(-/-) and IRF-1(-/-) hepatic cells compared with wild-type hepatic cells. These findings suggest that in addition to induction of apoptosis, previously well documented, IFN-gamma also stimulated hepatocytes, sinusoidal endothelial cells, and Kupffer cells partly via an STAT1/IRF-1-dependent mechanism to produce multiple chemokines and adhesive molecules responsible for promoting infiltration of leukocytes and, ultimately, resulting in hepatitis.

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

“…We identified hepatocytes and LSECs as CXCR3 ligand-producing cells upon Con A challenge in vivo and thus demonstrated their involvement in CXCR3 + lymphocyte recruitment. In this context, Jaruga et al (16) reported that IFN-g treatment induces the expression of several chemokines in primary hepatocytes, LSECs, and Kupffer cells through activation of STAT1, STAT3, and IFN regulatory factor 1. Accordingly, the lack of IFN regulatory factor 1 resulted in protection against Con A-induced hepatitis due to suppressed chemokine expression (among others, CXCL9, CXCL10, and CXCL11) and decreased leukocyte infiltration into the liver (16).…”

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

“…Here, we demonstrated that NK cells were the effectors to mediate the over-sensitive liver injury in an IFN-c-dependent manner in HBsAg transgenic mice. As demonstrated in ConA-induced hepatitis or LPS/D-galactosamineinduced liver damage, IFN-c plays an important role in the development of hepatic inflammation and liver injury through induction of chemokines, adhesive molecules, and proapoptotic proteins by activation of STAT1 [29,[43][44][45][46]. We observed higher expressions of IFN-c receptor on hepatocytes of HBsAg transgenic mice and stronger IFN-c signaling of pSTAT1-IRF-1, which might account for the hypersensitivity to IFN-cinduced hepatocyte injury in HBsAg transgenic mice (Fig.…”

“…The isolation and culture of primary mouse hepatocytes were performed as described [29]. Followed by treatment with IFN-c for various time periods, downstream signals of hepatocytes were determined by Western blotting.…”

Glycogen Synthase Kinase-3 Facilitates Con A-Induced IFN-γ–Mediated Immune Hepatic Injury

“…IFN-g-deficient mice (14) or mice treated with an IFN-gneutralizing Ab (12,21) show resistance to Con A-induced hepatic injury, as the IFN-g/STAT1/IRF-1 pathway is crucial for leukocyte infiltration and the expression of multiple cytokines, chemokines, and adhesive molecules (24). Consistent with these findings, we confirmed that Con A hepatic injury was attenuated in Ifngr1 2/2 mice, suggesting the important role of IFN-g signaling.…”

“…Evidence suggests that mice deficient in IFN-g and STAT1 are resistant to Con A-induced hepatic injury (14,22,23). IFN-g stimulation activates hepatocytes, sinusoidal endothelium, and Kupffer cells through a STAT1-dependent pathway to produce chemokines, including monokine induced by IFN-g, CCL-20, ENA-78 (epithelial cell-derived neutrophil-activating peptide), and adhesion molecules such as intracellular adhesion molecule-1 (CD54) and VCAM-1 (CD106), which may promote leukocyte infiltration into the liver (24). Additionally, treatment with IFN-g causes upregulation of CD95 in hepatocytes, followed by NKT-derived, CD95 ligand/CD95-mediated hepatic cell death and Con A-induced hepatic injury (14,(25)(26)(27)(28).…”