Proapoptotic Effects of the Chemokine, CXCL 10 Are Mediated by the Noncognate Receptor TLR4 in Hepatocytes

Abstract

Aberrant expression of the chemokine CXC chemokine ligand (CXCL)10 has been linked to the severity of hepatitis C virus (HCV)-induced liver injury, but the underlying molecular mechanisms remain unclear. In this study, we describe a yet-unknown proapoptotic effect of CXCL10 in hepatocytes, which is not mediated through its cognate chemokine receptor, but the lipopolysaccharide receptor Toll-like receptor 4 (TLR4). To this end, we investigated the link of CXCL10 expression with apoptosis in HCV-infected patients and in murine liver injury models. Mice were treated with CXCL10 or neutralizing antibody to systematically analyze effects on hepatocellular apoptosis in vivo. Direct proapoptotic functions of CXCL10 on different liver cell types were evaluated in detail in vitro. The results showed that CXCL10 expression was positively correlated with liver cell apoptosis in humans and mice. Neutralization of CXCL10 ameliorated concanavalin A-induced tissue injury in vivo, which was strongly associated with reduced liver cell apoptosis. In vitro, CXCL10 mediated the apoptosis of hepatocytes involving TLR4, but not CXC chemokine receptor 3 signaling. Specifically, CXCL10 induced long-term protein kinase B and Jun N-terminal kinase activation, leading to hepatocyte apoptosis by caspase-8, caspase-3, and p21-activated kinase 2 cleavage. Accordingly, systemic application of CXCL10 led to TLR4-induced liver cell apoptosis in vivo. Conclusion: The results identify CXCL10 and its noncognate receptor, TLR4, as a proapoptotic signaling cascade during liver injury. Antagonism of the CXCL10/TLR4 pathway might be a therapeutic option in liver diseases associated with increased apoptosis. (HEPATOLOGY 2013;57:797-805)

CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt

“…In vitro studies have shown that liver resident cells (e.g. hepatocytes, Kupffer cells, hepatic stellate cells) express these chemokines as a response to cellular injury and stress [20][21][22][23][24][25], suggesting a hepatic release of these chemokines. However, it was also implicated that circulating immune cells might contribute to elevated chemokine levels [23,29].…”

“…In particular, CXCR3 ligands, especially CXCL9, are increased during liver diseases [5][6][7][8][9][10][11][12] and are functionally linked to hepatic injury, inflammation, fibrosis, [8][9][10][12][13][14][15][16][17][18], angiogenesis [6] and complications of cirrhosis [19]. Liver resident cells, such as hepatocytes, Kupffer cells and hepatic stellate cells were found to represent a major source of CXCR3 ligands in the liver [20][21][22][23][24][25]. The increased intrahepatic levels of CXCR3 ligands during liver disease are also paralleled by elevated serum levels, as demonstrated in various animal and human studies [8,11,13,14,[16][17][18][19][26][27][28].…”

Elevation of Alanine Aminotransferase Activity Occurs after Activation of the Cell-Death Signaling Initiated by Pattern-Recognition Receptors ‎but before Activation of Cytolytic Effectors in NK or CD8+ T Cells in the Liver During Acute HCV Infection

“…Up-regulation of type III IFN, IL-28 and IL-29 mRNA were detected in liver and increased levels of IL-28 and IL-29 protein in serum of chimpanzees with acute HCV infection [20, 21]. RIG-I, TLR3, and TLR7, and induce interferons, cytokines, and chemokines during HCV infection [36, 37]. RIG-I mediated IFN response was shown to play an important role in controlling virus infection in HCV-infected cells [38].…”

Roles for Chemokines in Liver Disease

“…It has recently been shown that CXCL10 expression correlates with the degree of apoptosis in patients with hepatitis C and that this action is mediated by activation of the noncognate receptor TLR-4. 42 Intrahepatic and even serum CXCL10 levels have been reproducibly associated with the extent of HCV-induced liver fibrosis. [43][44][45][46][47] Circulating CXCL10 is also an independent biomarker for the recurrence of significant fibrosis after liver transplantation in HCV-infected patients.…”