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.
J Biomed Sci
; 31(1): 54, 2024 May 24.
Article
em En
| MEDLINE
| ID: mdl-38790021
ABSTRACT
BACKGROUND:
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.METHODS:
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.RESULTS:
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.CONCLUSIONS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Moléculas de Adesão Celular
/
Receptores de Hialuronatos
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Cirrose Hepática
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Hepatopatias Alcoólicas
Limite:
Animals
Idioma:
En
Revista:
J Biomed Sci
Assunto da revista:
MEDICINA
Ano de publicação:
2024
Tipo de documento:
Article