한빛사논문
Jinsol Han1, Chanbin Lee1,2, Hayeong Jeong1, Seunghee Jeon1, Myunggyo Lee4, Haeseung Lee4, Yung Hyun Choi5 and Youngmi Jung1,3*
1Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea.
2Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea.
3Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Republic of Korea.
4Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Pusan 46241, Republic of Korea.
5Department of Biochemistry, Dong-Eui University College of Korean Medicine, Pusan 47227, Republic of Korea.
*Correspondence: Youngmi Jung
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.
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