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.

IF 9 2区 医学 Q1 CELL BIOLOGY
Jinsol Han, Chanbin Lee, Hayeong Jeong, Seunghee Jeon, Myunggyo Lee, Haeseung Lee, Yung Hyun Choi, Youngmi Jung
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引用次数: 0

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.

肿瘤坏死因子诱导基因 6 蛋白及其衍生肽可抑制 CD44 在酒精相关肝病小鼠体内的激活,从而改善肝纤维化。
背景:酒精相关肝病(ALD)是全球关注的主要健康问题,但目前仍缺乏治疗ALD的有效疗法。肿瘤坏死因子诱导基因6蛋白(TSG-6)是间充质干细胞释放的一种细胞因子,已被证明可减少肝纤维化并促进慢性损伤肝脏的小鼠成功修复肝脏。然而,TSG-6在ALD中的作用及其机制仍不甚明了:为了研究TSG-6在伴有肝纤维化的ALD小鼠中的功能,长期喂食含乙醇(EtOH)食物9周的雄性小鼠再接受TSG-6(EtOH + TSG-6)或PBS(EtOH + Veh)治疗3周:结果:以TSG-6处理的小鼠喂食EtOH后,EtOH处理小鼠的严重肝损伤明显减轻。EtOH+TSG-6组的肝纤维化程度低于EtOH+Veh组。据报道,分化簇 44(CD44)的激活可促进造血干细胞的活化。CD44和核CD44胞内结构域(ICD)是CD44激活剂,在活化的造血干细胞和ALD小鼠中上调,而在喂食EtOH的TSG-6暴露小鼠中则显著下调。TSG-6与MMP14(一种能裂解CD44的蛋白水解酶)的催化位点直接相互作用,抑制了CD44裂解为CD44ICD,减少了ALD小鼠的造血干细胞活化和肝纤维化。此外,一种新型多肽的设计包含了一个与MMP14催化位点结合的区域,它能抑制CD44的活化,减轻酒精诱导的小鼠肝损伤,包括肝纤维化:这些结果表明,TSG-6可通过阻断CD44裂解为CD44ICD来减轻酒精诱导的肝损伤和纤维化,并表明TSG-6和TSG-6模拟肽可用作治疗ALD伴纤维化的药物。
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来源期刊
Journal of Biomedical Science
Journal of Biomedical Science 医学-医学:研究与实验
CiteScore
18.50
自引率
0.90%
发文量
95
审稿时长
1 months
期刊介绍: The Journal of Biomedical Science is an open access, peer-reviewed journal that focuses on fundamental and molecular aspects of basic medical sciences. It emphasizes molecular studies of biomedical problems and mechanisms. The National Science and Technology Council (NSTC), Taiwan supports the journal and covers the publication costs for accepted articles. The journal aims to provide an international platform for interdisciplinary discussions and contribute to the advancement of medicine. It benefits both readers and authors by accelerating the dissemination of research information and providing maximum access to scholarly communication. All articles published in the Journal of Biomedical Science are included in various databases such as Biological Abstracts, BIOSIS, CABI, CAS, Citebase, Current contents, DOAJ, Embase, EmBiology, and Global Health, among others.
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