Dishevelled2 promotes apoptosis and inhibits inflammatory cytokine secretion in rheumatoid arthritis fibroblast-like synoviocytes through crosstalk with the NF-κB pathway.

Xing Zhen Liu,Shu Peng Liu,Chen Guang Bai,Xiao Dan Gu,Ye Qing Shi,Ke Qi,Lan Ling Zhang,Jie Fan,Dong Bao Zhao,Jia Li,Wei Dong Xu,Ying Gao

doi:10.18632/oncotarget.15172

Abstract

Dishevelled (Dvl) not only links the canonical Wnt and non-canonical Wnt pathways but can also crosstalk with other pathways. As there is no systematic study to date on Dvl in rheumatoid arthritis (RA), we explored the impact of Dvl2 on proliferation and inflammatory cytokine secretion in RA fibroblast-like synoviocytes (FLSs). Expression of Dvl2 in RA synovial tissue and RA-FLSs was measured. Dvl2 was overexpressed in collagen-induced arthritis rats and human RA-FLSs,. the apoptosis and secretion of inflammatory cytokines were observed. Genetic changes and corresponding mechanisms caused by overexpressing Dvl2 in RA-FLSs were assessed. Dvl2 was found to be overexpressed in RA synovial tissue and RA-FLSs. Overexpression of Dvl2 increased apoptosis and inhibited inflammatory cytokine secretion by RA-FLSs in vivo and in vitro, and Dvl2 inhibited expression of anti-apoptotic and inflammatory genes. One possible mechanism is that Dvl2 decreases the nuclear translocation of P65 and inhibits its ability to bind to the promoters of NF-κB target genes. Our findings reveal an underappreciated role of Dvl2 in regulating inflammation and RA-FLS apoptosis and provide insight into crosstalk between the Wnt and nuclear factor-κB (NF-κB) pathways.

Highlights

Rheumatoid arthritis (RA) is a systemic and chronic inflammatory disease characterized by severe synovial hyperplasia and inflammation
A previous study demonstrated that β-catenin is upregulated in RA synovial tissue and RA-fibroblast-like synoviocytes (FLSs) and that this contributes to stable activation of the Wnt/βcatenin pathway in these cells [24]
Dvl2 overexpression has been shown to contribute to cell survival and proliferation [27, 28], our data support an underappreciated role of Dvl2 in promoting apoptosis and inhibiting the secretion of inflammatory cytokines in RA fibroblast-like synoviocytes (RA-FLSs)

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic and chronic inflammatory disease characterized by severe synovial hyperplasia and inflammation. Several signaling pathways are involved in the pathogenesis of synovitis, with the nuclear factor-κB (NF-κB) pathway being the most important [2, 3]. Targeting the NF-κB pathway is an important therapeutic strategy for RA, and inhibiting NF-κB (with anti-tumor necrosis factor(TNF) drugs) has shown good safety and efficacy in the treatment of this disease [4, 5]. In addition to the NF-κB pathway, the Wnt pathway, which is involved in organogenesis, cell proliferation, and tumorigenesis [6, 7], has an important function in the activation of RA-FLSs [8]. The Wnt pathway can be subdivided into β-catenin-dependent (Wnt/β-catenin) and β-catenin-independent (Wnt-planar cell polarity (Wnt-PCP) and Wnt-calcium (Wnt-Ca2+)) pathways [9]. In the Wnt-PCP pathway, Wnt stimulates the small G protein RHO and RHO-

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