Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6156071 | Translational Research | 2016 | 15 Pages |
Abstract
Fibrosis is the result of the abnormal accumulation of the extracellular matrix and ineffective clearance of fibroplasia. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are immunosuppressive lymphocytes that are highly expressed in the fibrotic tissues and peripheral blood of patients with cirrhosis or hepatocellular carcinoma. The role of Tregs in the progression of liver fibrosis is not well understood. Our experiments reveal that abundant of Tregs was scattered around sites of fibroplasia. Conversely, the depletion of Tregs promoted the resolution of liver fibrosis. As a consequence of Tregs depletion, the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) was altered; mmp9 and timp1 were reduced, whereas mmp2 and mmp14 were enhanced. The mmp9/timp1, mmp13/timp1, and mmp14/timp2 ratios were significantly increased in association with fibrosis resolution. Kupffer cells (KCs) are the main source of MMP. We observed that when KCs were cocultured with Tregs, the Tregs were able to inhibit MMP expression of KCs even at a low ratio; and anti-transforming growth factor-β (TGF-β) significantly reversed the inhibition of Tregs on MMP. Meanwhile, we also found that after Tregs depletion, TGF-β levels decreased in the mice liver, unlike in fibrosis. Furthermore, double depletion of both KCs and Tregs did not cause fiber resolution in mice. Thus, our results demonstrate that the persistence of liver cirrhosis is maintained by increased Tregs in the sites of fibroplasia and the subsequent regulation of the MMP/TIMP balance and that the suppression of KC-mediated MMP expression contributed to the regulatory process.
Keywords
PSCCytotoxic T-lymphocyte–associated protein 4CTLA-4TGF-βGlucocorticoid-induced TNF receptorGITRMNCsHSCsDulbecco Modified Eagle MediumKCSTregsCCl4CTLSDSDMEMECMα-SMAMMPPBSFACSLPSHCCα-smooth muscle actintransforming growth factor-βTIMPsodium dodecyl sulfateregulatory T cellsKupffer cellsMononuclear cellsHepatic stellate cellsPhosphate buffered salinefluorescence activated cell sortingcytotoxic lymphocytelipopolysaccharideExtracellular matrixmatrix metalloproteinaseTissue inhibitors of metalloproteinaseHepatocellular carcinomaCarbon tetrachloridePrimary sclerosing cholangitis
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Authors
Xiaohui Zhang, Min Feng, Xin Liu, Li Bai, Ming Kong, Yu Chen, Sujun Zheng, Shuang Liu, Yu-Jui Yvonne Wan, Zhongping Duan, Yuan-Ping Han,