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首页> 外文学位 >Expression of CD13/Aminopeptidase N by Synovial Fibroblasts: Novel Roles in the Pathogenesis of Rheumatoid Arthritis.
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Expression of CD13/Aminopeptidase N by Synovial Fibroblasts: Novel Roles in the Pathogenesis of Rheumatoid Arthritis.

机译：滑膜成纤维细胞表达CD13 /氨基肽酶N：类风湿关节炎发病中的新作用。

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摘要

Aminopeptidase N/CD13 is a metallopeptidase that is highly expressed by fibroblast-like synoviocytes (FLS) and may play a role in rheumatoid arthritis (RA). The goal of this study was to define CD13 function in the RA joint by monitoring CD13 expression in vivo and in vitro, analyzing regulation by pro-inflammatory cytokines of CD13 expression on FLS, describing the mechanisms by which CD13 is released from FLS, and defining potential roles for CD13 in homing of T cells to the RA joint and in regulating the growth and migration of RA FLS. In overview, we find that CD13 is expressed in synovial fluids, sera, FLS lysates, and culture supernatants as measured by ELISA, with a significant increase of CD13 in RA synovial fluids when compared to osteoarthritis. In FLS, pro-inflammatory cytokines (TNFalpha, IFNgamma, IL-17) are able to upregulate CD13 mRNA. However, as surface expression of CD13 did not correlate with CD13 mRNA, and soluble CD13 is present in RA synovial fluid, potential mechanisms for CD13 release from FLS were examined. CD13 was detected in sera, synovial fluids, and FLS culture supernatants, on extracellular vesicles and in soluble form. The release of soluble CD13 from FLS could be blocked by metalloproteinase inhibitors and siRNA directed against MT1-MMP/MMP14. With regard to biological functions, recombinant human CD13 was chemotactic for cytokine activated T-cells (Tck) through a G-protein-coupled receptor and contributed to the chemotactic properties of synovial fluid independently of enzymatic activity. Furthermore, inhibition of CD13 function in FLS, using enzymatic activity inhibitors or anti-CD13 antibodies, resulted in decreased growth and diminished migration of RAFLS. We conclude that CD13 is upregulated in the RA joint by pro-inflammatory cytokines where it is released on extracellular vesicles and shed as a soluble molecule from the FLS surface by metalloproteinases, including MMP14. Following its release from the FLS surface, CD13 induces chemotaxis of Tck, a T cell population similar to that found in RA synovium. Moreover, CD13 increases FLS growth and migration, thereby contributing to synovial hyperplasia in RA. Our data implicates CD13 in the pathogenesis of RA through enhancement of both T cell infiltration and aggressive FLS outgrowth.
机译：氨基肽酶N / CD13是一种金属肽酶，由成纤维细胞样滑膜细胞（FLS）高度表达，并可能在类风湿关节炎（RA）中起作用。这项研究的目的是通过监测体内和体外CD13的表达，分析CD13在FLS上的促炎细胞因子的调控，描述CD13从FLS释放的机制以及确定CD13在FLS中的表达来定义RA关节中CD13的功能。 CD13在将T细胞归巢到RA关节以及调节RA FLS的生长和迁移中的潜在作用。总的来说，我们发现CD13在滑液，血清，FLS裂解物和培养上清液中表达（通过ELISA法测定），与骨关节炎相比，RA滑液中CD13明显增加。在FLS中，促炎性细胞因子（TNFα，IFNγ，IL-17）能够上调CD13 mRNA。但是，由于CD13的表面表达与CD13 mRNA不相关，并且RA滑液中存在可溶性CD13，因此研究了CD13从FLS释放的潜在机制。在血清，滑液和FLS培养上清液中，细胞外囊泡上和可溶形式检测到CD13。金属蛋白酶抑制剂和针对MT1-MMP / MMP14的siRNA可以阻止FLS中可溶性CD13的释放。在生物学功能方面，重组人CD13通过G蛋白偶联受体对细胞因子激活的T细胞（Tck）具有趋化作用，并且对滑液的趋化特性有贡献，而与酶促活性无关。此外，使用酶活性抑制剂或抗CD13抗体抑制FLS中CD13的功能会导致RAFLS的生长减少和迁移减少。我们得出的结论是CD13在促炎性细胞因子在RA关节中被上调，在CD13中CD13在细胞外囊泡中释放，并通过可溶性金属蛋白酶（包括MMP14）作为可溶性分子从FLS表面脱落。从FLS表面释放后，CD13诱导Tck趋化，Tck是一种类似于RA滑膜中的T细胞。而且，CD13增加FLS的生长和迁移，从而导致RA中的滑膜增生。我们的数据通过增强T细胞浸润和侵略性FLS增生将CD13牵连到RA的发病机理中。

著录项

  • 作者

    Morgan, Rachel L.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Immunology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 193 p.
  • 总页数 193
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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