TNFα, PDGF, and TGFβ synergistically induce synovial lining hyperplasia via inducible PI3Kδ
| Autor: | Hiroyuki Yoshitomi, Koichi Murata, Moritoshi Furu, Takayuki Fujii, Masahiro Ishikawa, Hideyuki Shibuya, Hiromu Ito, Shio Kobayashi, Shuichi Matsuda |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
medicine.medical_specialty
MMP3 animal structures medicine.medical_treatment PI3Kδ Arthritis Rheumatoid TGFβ Rheumatology Downregulation and upregulation Transforming Growth Factor beta Internal medicine medicine Humans Fibroblast-like synoviocytes RNA Small Interfering Cells Cultured PI3K/AKT/mTOR pathway Platelet-Derived Growth Factor Hyperplasia Phosphoinositide 3-kinase biology Tumor Necrosis Factor-alpha Growth factor Synovial Membrane PDGF Cadherins Up-Regulation Endocrinology PI3K/Akt pathway embryonic structures biology.protein Cancer research Matrix Metalloproteinase 3 Tumor necrosis factor alpha Phosphatidylinositol 3-Kinase Platelet-derived growth factor receptor Signal Transduction Transforming growth factor |
| Zdroj: | Modern Rheumatology. 25:72-78 |
| ISSN: | 1439-7609 1439-7595 |
| DOI: | 10.3109/14397595.2014.900847 |
| Popis: | Objectives. To determine the mechanism underlying hypertrophic synovium in rheumatoid arthritis (RA). Methods. We examined micromass cultures of fibroblast-like synoviocytes (FLSs) stimulated with tumor necrosis factor α (TNFα), platelet-derived growth factor (PDGF), and/or transforming growth factor β (TGFβ). The hypertrophic architecture of the micromasses, expression of phosphoinositide 3 kinase (PI3K) isoforms, and persistent activation of PI3K-Akt pathways were investigated. FLSs transfected with siRNA were also examined in the micromass cultures. Results. The combination of TNFα, PDGF, and TGFβ (TPT condition) induced obvious hypertrophic architecture of the intimal lining layer in FLSs in micromass cultures, and was accompanied by upregulated expression of matrix metalloproteinase-3 (MMP3), Cadherin-11, and PI3Kδ. In monolayer FLSs, the TPT condition enhanced the expression of PI3Kδ and persistent activation of the PI3K-Akt pathway. Knockdown of PI3Kδ significantly inhibited the formation of the hypertrophic synovial lining in the TPT condition. Conclusions. These results collectively indicate that inducible PI3Kδ plays a crucial role in persistent activation of PI3K-Akt in FLSs, and in the formation of a hypertrophic synovial lining. PI3Kδ may be an alternative treatment target for the regulation of proliferative synovium in RA. Published by Informa Healthcare for the Japan Rheumatism Association |
| Databáze: | OpenAIRE |
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