| 3 | Extracellular sulfatase-2 is overexpressed in rheumatoid arthritis and mediates the TNF-α-induced inflammatory activation of synovial fibroblasts显示文摘Extracellular sulfatase-2(Sulf-2)influences receptor-ligand binding and subsequent signaling by chemokines and growth factors,yet Sulf-2 remains unexplored in inflammatory cytokine signaling in the context of rheumatoid arthritis(RA).In the present study,we characterized Sulf-2 expression in RA and investigated its potential role in TNF-α-induced synovial inflammation using primary human RA synovial fibroblasts(RASFs).Sulf-2 expression was significantly higher in serum and synovial tissues from patients with RA and in synovium and serum from hTNFtg mice.RNA sequencing analysis of TNF-α-stimulated RASFs showed that Sulf-2 siRNA modulated~2500 genes compared to scrambled siRNA.Ingenuity Pathway Analysis of RNA sequencing data identified Sulf-2 as a primary target in fibroblasts and macrophages in RA.Western blot,ELISA,and qRT‒PCR analyses confirmed that Sulf-2 knockdown reduced the TNF-α-induced expression of ICAM1,VCAM1,CAD11,PDPN,CCL5,CX3CL1,CXCL10,and CXCL11.Signaling studies identified the protein kinase C-delta(PKCδ)and c-Jun N-terminal kinase(JNK)pathways as key in the TNF-α-mediated induction of proteins related to cellular adhesion and invasion.Knockdown of Sulf-2 abrogated TNF-α-induced RASF proliferation.Sulf-2 knockdown with siRNA and inhibition by OKN-007 suppressed the TNF-α-induced phosphorylation of PKCδand JNK,thereby suppressing the nuclear translocation and DNA binding activity of the transcription factors AP-1 and NF-κBp65 in human RASFs.Interestingly,Sulf-2 expression positively correlated with the expression of TNF receptor 1,and coimmunoprecipitation assays demonstrated the binding of these two proteins,suggesting they exhibit crosstalk in TNF-αsignaling.This study identified a novel role of Sulf-2 in TNF-αsignaling and the activation of RA synoviocytes,providing the rationale for evaluating the therapeutic targeting of Sulf-2 in preclinical models of RA. | Ruby J.Siegel Anil K.Singh Paul M.Panipinto Farheen S.Shaikh Judy Vinh Sang U.Han H.Mark Kenney Edward M.Schwarz Cynthia S.Crowson Sadik A.Khuder Basil S.Khuder David A.Fox Salahuddin Ahmed | 2022 | Cellular & Molecular Immunology2022，19，10： | 0 |
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