We are analyzing https://link.springer.com/article/10.1186/ar2981.

Title:
Platelet-derived growth factor and transforming growth factor beta synergistically potentiate inflammatory mediator synthesis by fibroblast-like synoviocytes | Arthritis Research & Therapy
Description:
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 phosphoinositide 3-kinase (PI3K) signaling pathways were induced for at least four hours by 2GF, as demonstrated by persistently upregulated levels of phospho-Akt and phospho-ERK. However, pharmacologic inhibitor studies demonstrated that the potentiating action of 2GF was dependent on PI3 kinase only, and not on ERK. Conclusions The combination of PDGF and TGF-β dramatically potentiates FLS response to cytokines in a receptor-mediated and PI3 kinase-dependent fashion. These data suggest that 2GF contribute to synovitis by directing synovial fibroblasts toward a more aggressive phenotype in response to TNFα. Therefore, inhibition of growth factor signaling may constitute a complementary therapeutic approach to cytokine-targeted treatments for RA.
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growth, fls, tnfα, pubmed, article, figure, google, scholar, arthritis, cas, factor, effect, imatinib, expression, tgfβ, secretion, rheumatoid, pdgf, mmp, synovial, factors, hours, data, induced, signaling, mesylate, added, pik, kinase, combination, transforming, inflammatory, cytokines, usa, fibroblastlike, gene, mipα, addition, time, plateletderived, effects, erk, inhibitor, studies, cells, mrna, synoviocytes, mediators, tnfαinduced, central,

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tumour necrosis factor-alpha granulocyte–macrophage colony-stimulating factor secondary anti-rabbit-igg-hrp transforming growth factor-beta tumor necrosis factor-alpha platelet-derived growth factor transforming growth factor-beta1 ras-raf-mek-erk pathways [30 platelet-derived growth factors article download pdf nf-kappab-mediated transcriptional repression post-hoc test comparing growth factor-induced synergy pi3-kinase/akt-dependent pathways smad tgf-beta pathway bcr-abl positive cells growth factor receptors extracellular-signal-regulated kinase extracellular signal-regulated kinase growth factor signaling potentiate tnfα-induced il6 small gtp-binding protein biorad bio-plex assays cells expressing bcr-abl cytokine-induced gene expression pi3 kinase-dependent fashion tyrosine-kinase receptor activation tel-pdgfr fusion proteins c-kit tyrosine kinase translational research institute growth factor activation imatinib mesylate inhibits pi3k signalling tnfα-induced gene expression chronic inflammatory arthritis induced low-level secretion tgf-β induced signaling growth factor combination tgf-β induce proliferation synergistically augmented tnfα tyrosine kinase inhibitor single time-point experiments cytokine-induced growth abl tyrosine kinase privacy choices/manage cookies authors’ original file inflammatory biomarker expression ra drug therapy full size image relative expression units

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