Abstract
Fas Ligand (FasL) and Fas (APO-1/CD95) are members of the TNFR superfamily and may trigger apoptosis. Here, we aimed to elucidate the functional role of Fas signaling in an experimental model of chronic liver disease, the hepatocyte-specific NEMO knockout (NEMOΔhepa) mice. We generated NEMOΔhepa /Faslpr mice, while NEMOΔhepa, NEMOf/f as well as Faslpranimals were used as controls, and characterized their phenotype during liver disease progression. Liver damage was evaluated by serum transaminases, histological, immunofluorescence procedures, and biochemical and molecular biology techniques. Proteins were detected by western Blot, expression of mRNA by RT-PCR, and infiltration of inflammatory cells was determined by FACs analysis, respectively. Faslpr mutation in NEMOΔhepa mice resulted in overall decreased liver injury, enhanced hepatocyte survival, and reduced proliferation at 8 weeks of age compared with NEMOΔhepa mice. Moreover, NEMOΔhepa/Faslpr animals elicited significantly decreased parameters of liver fibrosis, such as Collagen IA1, MMP2, and TIMP1, and reduced proinflammatory macrophages and cytokine expression. At 52 weeks of age, NEMOΔhepa/Faslpr exhibited less malignant growth as evidenced by reduced HCC burden associated with a significantly decreased number of nodules and LW/BW ratio and decreased myeloid populations. Deletion of TNFR1 further reduced tumor load of 52-weeks-old NEMOΔhepa/Faslpr mice. The functionality of FasL/Fas might affect inflammation-driven tumorigenesis in an experimental model of chronic liver disease. These results help to develop alternative therapeutic approaches and extend the limitations of tumor therapy against HCC.
Highlights
Introduction The transmembrane proteins FasLigand (FasL) and Fas (Fas/ CD95/APO-1) are members of the tumor necrosis factor (TNF) and TNF receptor gene superfamilies (TNFR gene superfamily), respectively, and are expressed in numerous cell types
Generation and characterization of the NEMOΔhepa/Faslpr mice To address the functional relevance of Fas Ligand (FasL)/Fas signaling for chronic disease progression in the
No neoplasia was present in the hepatic parenchyma of 8-week-old NEMOΔhepa/Faslpr livers markedly characterized by multifocal necrosis (Fig. 1a-d)
Summary
Introduction The transmembrane proteins FasLigand (FasL) and Fas (Fas/ CD95/APO-1) are members of the tumor necrosis factor (TNF) and TNF receptor gene superfamilies (TNFR gene superfamily), respectively, and are expressed in numerous cell types. Downregulation or loss of Fas expression and function is frequently found in the progression of a number of human malignancies, including colon, breast, lung, and liver carcinoma[3,4]. The FasL–Fas pathway plays a crucial role in tumor initiation and progression. It might be a plausible therapeutic target for progression of liver disease, and hepatocellular carcinoma (HCC). Escape from the immune surveillance may play an important role in liver tumorigenesis. Alteration of the FasL/Fas system is regarded as one of the mechanisms preventing the immune system from rejecting tumor cells[7]. Little attention has been paid to the role of the Fas/FasL interaction in vivo
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