Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: To examine the role of Signal Transducer and Activator of Transcription 3 (STAT3) in mediating synovial cell-cell interactions, migration/invasion and key downstream signaling pathways in the inflamed synovial tissue.
Methods: Phospho-STAT3 (p-STAT3) expression in synovial tissue was quantified by immunohistology/immunoflourecence and Western blot. Notch-1 IC, HIF1α, p-STAT3 and total-STAT3 protein levels were assessed in synovial fibroblasts under normoxic and hypoxic (3%) conditions by Western Blot. In parallel gene expression of the Notch-1 receptor, its ligand DLL-4 and downstream target genes (hrt-1, hrt-2) were quantified by Real-time PCR. Synovial fibroblast migration, invasion, matrigel network formation and MMP2/9 in-gel zymography were quantified under normoxic and hypoxic (3%) conditions in the presence of STAT3 inhibitor (WP1066). Using RA synovial explants ex-vivo, the effect of the STAT3 inhibitor (WP1066) on IL-6, IL-8 and IL-10 expression were assessed by ELISA.
Results: Nuclear expression of p-STAT3 was demonstrated in RA synovial tissue, localised to the sub-lining and lining layer regions. p-STAT3 expression was significantly higher in inflamed synovial tissue compared to normal synovial tissue. Hypoxia (3%) induced p-STAT3, Notch-1 IC, HIF1α protein expression in synovial fibroblasts, an effect that was inhibited by the presence of WP1066. Similarly hypoxia-induced Notch-1 receptor, DLL-4 and hrt-1, hrt-2 gene expression were inhibited in the presence of WP1066. Functionally hypoxia-induced synovial fibroblast invasion, matrigel network formation, migration, and pro-MMP-2/-9 activities, were inhibited in the presence of STAT3 inhibitor. Finally we demonstrated in RA synovial explants ex-vivo that WP1066 significantly decreased IL-6, IL-8 expression and significantly increased anti-inflammatory cytokine IL-10 expression.
Conclusion: p–STAT3 is increased in RA synovial tissue and mediates synovial fibroblast migrational and invasive processes. Furthermore these effects may in part be mediated through Notch-1/HIF1α interactions.
Disclosure:
W. Gao,
None;
D. J. Veale,
Abbott Laboratories,
2,
MSD,
2,
Opsona,
2,
Pfizer Inc,
2,
Roche Pharmaceuticals,
2;
U. Fearon,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/signal-transducer-and-activator-of-transcription-3-induced-synovial-invasion-and-migration-is-mediated-in-part-through-the-notchhypoxia-inducible-factor-1%ce%b1-pathways/