- 作者: Jinsol Han, Chanbin Lee, Hayeong Jeong, Seunghee Jeon, Myunggyo Lee, Haeseung Lee, Yung Hyun Choi & Youngmi Jung
- 作者服務機構: 1.Department of Biochemistry, Dong-Eui University College of Korean Medicine, Pusan, 47227, Republic of Korea 2.Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan, 46241, Republic of Korea 3.Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan, 46241, Republic of Korea 4.Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Pusan, 46241, Republic of Korea 5.Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan, 46241, Republic of Korea
- 中文摘要:
- 英文摘要:
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. - 中文關鍵字:
- 英文關鍵字: Alcohol-related liver disease, Liver fbrosis, Tumor necrosis factor-inducible gene 6 protein, Cluster of diferentiation 44