1. Transcription Factor NFAT5 Promotes Migration and Invasion of Rheumatoid Synoviocytes via Coagulation Factor III and CCL2.
- Author
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Lee S, Kong JS, You S, Kwon HM, Yoo SA, Cho CS, and Kim WU
- Subjects
- Aged, Animals, Arthritis, Rheumatoid pathology, Cells, Cultured, Female, Humans, Interleukin-1beta metabolism, Male, Mice, Mice, Knockout, Middle Aged, Signal Transduction physiology, Synovial Membrane metabolism, Synovial Membrane pathology, Synoviocytes pathology, Transcriptome physiology, Transforming Growth Factor beta metabolism, Up-Regulation physiology, Arthritis, Rheumatoid metabolism, Cell Movement physiology, Chemokine CCL2 metabolism, Neoplasm Invasiveness pathology, Synoviocytes metabolism, Thromboplastin metabolism, Transcription Factors metabolism
- Abstract
Fibroblast-like synoviocytes (FLSs) play a key role in the progression of rheumatoid arthritis (RA) as a primary component of invasive hypertrophied pannus. FLSs of RA patients (RA-FLSs) exhibit cancer-like features, including promigratory and proinvasive activities that largely contribute to joint cartilage and bone destruction. In this study, we hypothesized that the NF of activated T cell 5 (NFAT5), a transcription factor involving tumor invasiveness, would control the migration and invasion of RA-FLSs. Analyses of transcriptomes demonstrated the significant involvement of NFAT5 in locomotion of RA-FLSs and that tissue factor (TF; also known as coagulation factor III) and CCL2 were the major downstream target genes of NFAT5 involving FLS migration and invasion. In cultured RA-FLSs, IL-1β and TGF-β increased TF and CCL2 expression by upregulating NFAT5 expression via p38 MAPK. Functional assays demonstrated that NFAT5- or TF-deficient RA-FLSs displayed decreased lamellipodia formation, cell migration, and invasion under IL-1β- or TGF-β-stimulated conditions. Conversely, factor VIIa, a specific activator of TF, increased migration of RA-FLSs, which was blocked by NFAT5 knockdown. Recombinant CCL2 partially restored the decrease in migration and invasion of NFAT5-deficient RA-FLSs stimulated with IL-1β. NFAT5-knockout mouse FLSs also showed decreased expressions of TF and CCL2 and reduced cell migration. Moreover, KRN2, a specific inhibitor of NFAT5, suppressed migration of FLSs stimulated with TGF-β. Conclusively, to our knowledge, this is the first study to provide evidence of a functional link between osmoprotective NFAT5 and TF in the migration and invasion of RA-FLSs and supports a role for NFAT5 blockade in the treatment of RA., (Copyright © 2018 by The American Association of Immunologists, Inc.)
- Published
- 2018
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