https://scholars.lib.ntu.edu.tw/handle/123456789/563924
標題: | Soluble Dipeptidyl Peptidase-4 Induces Fibroblast Activation Through Proteinase-Activated Receptor-2 | 作者: | Lee S.-Y. Wu S.-T. Liang Y.-J. MING-JAI SU Huang C.-W. Jao Y.-H. Ku H.-C. |
關鍵字: | dipeptidyl peptidase-4; fibroblast; fibrosis; nuclear factor-kappa B; proteinase-activated receptor-2; suppressor of mothers against decapentaplegic | 公開日期: | 2020 | 卷: | 11 | 起(迄)頁: | 552818 | 來源出版物: | Frontiers in Pharmacology | 摘要: | Fibroblasts are the chief secretory cells of the extracellular matrix (ECM) responsible for basal deposition and degradation of the ECM under normal conditions. During stress, fibroblasts undergo continuous activation, which is defined as the differentiation of fibroblasts into myofibroblasts, a cell type with an elevated capacity for secreting ECM proteins. Dipeptidyl peptidase-4 (DPP4) is a ubiquitously expressed transmembrane glycoprotein and exerts effects that are both dependent and independent of its enzymatic activity. DPP4 has been demonstrated to define fibroblast populations in human skin biopsies of systemic sclerosis. Shedding of DPP4 from different tissues into the circulation appears to be involved in the pathogenesis of the diseases. The mechanism underlying soluble DPP4–induced dermal fibrosis has not been clearly determined. The effects of DPP4 on murine 3T3 fibroblasts and human dermal fibroblasts were evaluated by measuring the expression of fibrotic proteins, such as α-SMA and collagen. Soluble DPP4 stimulated the activation of fibroblasts in a dose-dependent manner by activating nuclear factor-kappa B (NF-κB) and suppressor of mothers against decapentaplegic (SMAD) signaling. Blocking proteinase-activated receptor-2 (PAR2) abrogated the DPP4-induced activation of NF-κB and SMAD and expression of fibrosis-associated proteins in fibroblasts. Linagliptin, a clinically available DPP4 inhibitor, was observed to abrogate the soluble DPP4–induced expression of fibrotic proteins. This study demonstrated the mechanism underlying soluble DPP4, which activated NF-κB and SMAD signaling through PAR2, leading to fibroblast activation. Our data extend the current view of soluble DPP4. Elevated levels of circulating soluble DPP4 may contribute to one of the mediators that induce dermal fibrosis in patients. ? Copyright ? 2020 Lee, Wu, Liang, Su, Huang, Jao and Ku. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/563924 | ISSN: | 16639812 | DOI: | 10.3389/fphar.2020.552818 | SDG/關鍵字: | dipeptidyl peptidase IV; immunoglobulin enhancer binding protein; linagliptin; proteinase activated receptor 2; RNA; Smad protein; synaptotagmin I; adult; animal cell; animal cell culture; Article; cell activation; cell viability; controlled study; drug mechanism; fibroblast; human; human cell; human cell culture; immunofluorescence; mouse; NIH 3T3 cell line; nonhuman; protein expression; reverse transcription polymerase chain reaction; RNA extraction |
顯示於: | 藥理學科所 |
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