A COL1A1 Promoter-Controlled Expression of TGF-β Soluble Receptor Inhibits Hepatic Fibrosis Without Triggering Autoimmune Responses
A COL1A1 Promoter-Controlled Expression of TGF-β Soluble Receptor Inhibits Hepatic Fibrosis Without Triggering Autoimmune Responses
复制标题
DOI：
10.1007/s10620-018-5168-3
复制
发表时间：
2018-06
影响因子：
3.1
通讯作者：
Shouhua Zhang;Yuanqi Gong;Ju-hua Xiao;Yong Chai;Jun Lei;Hui Huang;T. Xiang;W. Shen
中科院分区：
文献类型：
--
作者：
Shouhua Zhang;Yuanqi Gong;Ju-hua Xiao;Yong Chai;Jun Lei;Hui Huang;T. Xiang;W. Shen
可溶型转化生长因子-β-I型受体(ST-β-RII)通过抑制转化生长因子-β-1的表达而抑制肝纤维化，但过量使用会引发自身免疫反应。目的检测转化生长因子-β-I型胶原启动子COL1A1通过与转化生长因子-β1水平的反馈环能否准确调控ST-βRII的表达。体外和体内检测对转化生长因子-β活性的抑制作用。检测总的和生物活性的转化生长因子-β，肝纤维化程度，α-β-SMA，胶原水平和肝功能。在体内外，Ad-Col-StβRII能显著抑制转化生长因子-β-1的活性，但不能完全抑制转化生长因子-β-1的活性，而Ad-Col-St-β-RII则几乎完全抑制转化生长因子--1的活性。从肝纤维化程度、α-SMA和肝组织胶原水平来看，Ad-COL-StβRII和Ad-CMV-StβRII在治疗肝纤维化方面具有相似的疗效。在肝功能恢复方面，Ad-COL-StβRII优于Ad-CMV-StβRII。结论COL1A1能准确调控STβRII的表达，抑制过度的生物活性β-β，从而抑制肝纤维化，但不诱导自身免疫反应。
BackgroundSoluble TGF-β1 type II receptor (sTβRII) via TGF-β1 inhibition could inhibit hepatic fibrosis, but over-dosage triggers autoimmune responses.AimTo test whether the use of a TGF-β1-responsive collagen I promoter COL1A1, via generating a feedback loop to TGF-β1 level, could offer accurate control on sTβRII expression.MethodsRecombinant adenoviruses with COL1A1 (Ad-COL-sTβRII/Luc) or CMV promoter (Ad-CMV-sTβRII/Luc) were constructed and characterized. Inhibition of TGF-β activity was determined both in vitro and in vivo. Total and bioactive TGF-β, hepatic fibrosis scale, α-SMA, collagen levels, and liver function were determined.ResultsCOL1A1, but not CMV, responded to TGF-β1 in vitro. Both in vitro and in vivo, Ad-COL-sTβRII could significantly, but not completely inhibit TGF-β1 activity while Ad-CMV-sTβRII almost completely inhibited TGF-β1 activity. As evidenced by fibrosis scale, α-SMA, and collagen levels in liver tissue, Ad-COL-sTβRII and Ad-CMV-sTβRII had comparable efficacies in treating hepatic fibrosis. Ad-COL-sTβRII was better than Ad-CMV-sTβRII in liver function restore. Ad-CMV-sTβRII, but not Ad-COL-sTβRII, induced high level of anti-dsDNA and anti-Sm antibodies in rats.ConclusionsCOL1A1 can precisely control sTβRII expression to inhibit excessive bioactive TGF-β level and thus inhibit hepatic fibrosis but without inducing autoimmune responses.