platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes血小板源生长因子、转化生长因子β协同加强纤维母synoviocytes炎性介质的合成.pdfVIP

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platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes血小板源生长因子、转化生长因子β协同加强纤维母synoviocytes炎性介质的合成.pdf

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platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes血小板源生长因子、转化生长因子β协同加强纤维母synoviocytes炎性介质的合成

Rosengren et al. Arthritis Research Therapy 2010, 12:R65 /content/12/2/R65 R E S E A R C H A R T I C L E Open Access Research article Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes Sanna Rosengren, Maripat Corr and David L Boyle* Abstract Introduction: The objective of this study was to model the effects of transforming growth factor beta (TGF-β) and platelet-derived growth factor (PDGF), both present in rheumatoid arthritis (RA) synovia, on the behavior of fibroblast- like synoviocytes (FLS) in response to pro-inflammatory cytokine (interleukin (IL)1β, tumor necrosis factor-alpha (TNFα)) challenge. Methods: Gene and protein expression by fibroblast-like synoviocytes in vitro was studied by quantitative Polymerase Chain Reaction (qPCR), ELISA and multiplex bead cytokine assays. Intracellular signaling pathway activation was determined by Western blot for phospho-kinases and the use of specific inhibitors. Results: In combination, TGF-β and PDGF (2GF) synergistically augmented TNFα- or IL1β-induced matrix metalloproteinase 3 (MMP3), IL6, IL8, and macrophage inflammatory protein 1 alpha (MIP1α) secretion by FLS. Other FLS-derived mediators remained unaffected. Individually, neither growth factor significantly potentiated TNFα or IL1β- induced MMP3 secretion, and only slightly enhanced IL6. The effect of 2GF on TNFα-induced gene expression was transcriptionally mediated; blocked by imatinib mesylate; and occurred even if 2GF was added as much as four hours prior to TNFα. In addition, a 15-minute pulse of 2GF four hours prior to TNFα stimulation yielded a synergistic response. The extracellular-signal-regulated kinase (ERK) and phosphoi nositide 3-kinase (PI3K) signaling pathways were induced for at least four h