Engler Anna, Tange Clare, Frank-Bertoncelj Mojca, Gay Renate E, Gay Steffen, Ospelt Caroline
Center of Experimental Rheumatology, Bio-Technopark Schlieren, University Hospital Zurich, Gloriastrasse 25, 8091 Zurich and Wagistrasse 14, 8952, Schlieren, Switzerland.
Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.
J Mol Med (Berl). 2016 Feb;94(2):173-82. doi: 10.1007/s00109-015-1332-9. Epub 2015 Aug 23.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells, SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study, we investigated the regulation, expression, and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNFα, but decreased upon treatment with cigarette smoke extract. Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1 modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can therefore promote progression of RA.
SIRT1 is upregulated by TNFα but decreased upon CSE treatment of RASF. Upregulation of SIRT1 in RA smokers correlates with increased leukocytic infiltration. SIRT1 modulates expression of genes regulating cell adhesion and inflammation. SIRT1 regulates proliferation of RASF.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征是滑膜关节的炎症和破坏。沉默调节蛋白（SIRT）1在RA中的作用尚无定论。在人类滑膜细胞中，SIRT1被证明可促进细胞因子产生和抗凋亡。然而，敲除SIRT1会加重小鼠的炎性关节炎，并增加小鼠巨噬细胞中促炎细胞因子的产生。在本研究中，我们调查了SIRT1在RA中的调节、表达和功能，特别是其在人RA滑膜成纤维细胞（RASF）黏附和增殖中的作用。我们发现，RA吸烟者滑膜组织中SIRT1在体内表达增加，在体外经TNFα刺激RASF后也增加，但经香烟烟雾提取物处理后降低。RA吸烟者的滑膜组织显示出更高的白细胞浸润，且与SIRT1水平升高呈正相关。全转录组分析显示，SIRT1调节参与炎症反应和细胞黏附调节的基因表达。在功能研究中，沉默SIRT1可降低RASF的增殖和白细胞黏附，但在调节对塑料的黏附方面结果不一致。总之，SIRT1调节RASF的增殖以及潜在的黏附特性，因此可促进RA的进展。
TNFα可上调SIRT1，但RASF经CSE处理后SIRT1降低。RA吸烟者中SIRT1的上调与白细胞浸润增加相关。SIRT1调节调节细胞黏附和炎症的基因表达。SIRT1调节RASF的增殖。
