Tumor necrosis factor-inducible gene 6 protein and its derived peptide ameliorate liver fibrosis by repressing CD44 activation in mice with alcohol-related liver disease

• Published in: Journal of biomedical science Vol. 31; no. 1; pp. 54 - 21
• Main Authors: Han, Jinsol, Lee, Chanbin, Jeong, Hayeong, Jeon, Seunghee, Lee, Myunggyo, Lee, Haeseung, Choi, Yung Hyun, Jung, Youngmi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24-05-2024; BioMed Central; BMC
• Subjects: Alcohol; Alcohol-related liver disease; Alcohols; Animals; Care and treatment; CD44 antigen; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cleavage; Cluster of differentiation 44; Damage; Ethanol; Fibrosis; Genetic aspects; Health aspects; Hepatitis; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Laboratory animals; Liver; Liver cirrhosis; Liver Cirrhosis - chemically induced; Liver Cirrhosis - drug therapy; Liver Cirrhosis - metabolism; Liver diseases; Liver Diseases, Alcoholic - drug therapy; Liver Diseases, Alcoholic - metabolism; Liver fibrosis; Male; Mesenchymal stem cells; Mice; Mice, Inbred C57BL; Peptide regulatory factors; Peptides; Peptides - metabolism; Peptides - pharmacology; Physiological aspects; Proteins; Proteolysis; Stem cells; Tumor necrosis factor; Tumor necrosis factor-inducible gene 6 protein; Tumor necrosis factor-TNF; South Korea; United States > US; Cluster of differentiation 44; Liver fibrosis; Tumor necrosis factor-inducible gene 6 protein; Alcohol-related liver disease
• ISSN: 1423-0127; 1021-7770; 1423-0127
• DOI: 10.1186/s12929-024-01042-5

Alcohol-related liver disease (ALD) is a major health concern worldwide, but effective therapeutics for ALD are still lacking. Tumor necrosis factor-inducible gene 6 protein (TSG-6), a cytokine released from mesenchymal stem cells, was shown to reduce liver fibrosis and promote successful liver repair in mice with chronically damaged livers. However, the effect of TSG-6 and the mechanism underlying its activity in ALD remain poorly understood.
To investigate its function in ALD mice with fibrosis, male mice chronically fed an ethanol (EtOH)-containing diet for 9 weeks were treated with TSG-6 (EtOH + TSG-6) or PBS (EtOH + Veh) for an additional 3 weeks.
Severe hepatic injury in EtOH-treated mice was markedly decreased in TSG-6-treated mice fed EtOH. The EtOH + TSG-6 group had less fibrosis than the EtOH + Veh group. Activation of cluster of differentiation 44 (CD44) was reported to promote HSC activation. CD44 and nuclear CD44 intracellular domain (ICD), a CD44 activator which were upregulated in activated HSCs and ALD mice were significantly downregulated in TSG-6-exposed mice fed EtOH. TSG-6 interacted directly with the catalytic site of MMP14, a proteolytic enzyme that cleaves CD44, inhibited CD44 cleavage to CD44ICD, and reduced HSC activation and liver fibrosis in ALD mice. In addition, a novel peptide designed to include a region that binds to the catalytic site of MMP14 suppressed CD44 activation and attenuated alcohol-induced liver injury, including fibrosis, in mice.
These results demonstrate that TSG-6 attenuates alcohol-induced liver damage and fibrosis by blocking CD44 cleavage to CD44ICD and suggest that TSG-6 and TSG-6-mimicking peptide could be used as therapeutics for ALD with fibrosis.