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THU0059 Oncostatin m induces inflammation and differentially regulates tnf alpha-induced pro-inflammatory mechanisms and notch signalling in the ra joint
  1. MM Hanlon1,
  2. D Veale2,
  3. S Wade1,
  4. M Biniecka2,
  5. U Fearon1,
  6. T McGarry1
  1. 1Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin
  2. 2Centre for Arthritis and Rheumatic Diseases, St Vincents University Hospital, University College Dublin, Dublin, Ireland


Background Oncostatin M (OSM) is a pleiotropic cytokine, highly expressed in the RA joint that displays both agonistic and antagonistic effects depending on the inflammatory microenvironment. This study examines the effect of OSM on inflammation, the Notch-1 signalling pathway which plays a critical role in vascular development and angiogenesis and finally on TNFα-induced pro-inflammatory mechanisms in Rheumatoid Arthritis.

Objectives To examine the effect of OSM on cytokine/chemokine production, angiogenesis and the Notch-1 signalling pathway in synovial fibroblasts and endothelial cells and whether OSM potentiates the effects of TNFα-induced pro-inflammatory effects.

Methods Primary RA synovial fibroblasts (RASFC) isolated from RA synovial biopsies obtained at time of knee arthroscopy and human dermal microvascular endothelial cells (HMVEC) were grown to confluence. RASFC and HMVEC were cultured with OSM (10ngml) alone or in combination with increasing concentrations of TNFα (0.01–1ng/ml). IL-6, IL-8, RANTES, GROα and MCP-1 cytokines/chemokines were quantified in culture supernatants by ELISA. Functionally, angiogenesis and invasion were assessed by matrigel tube formation and Transwell invasions assays respectively, and VEGF in cell lysates quantified by Real-time PCR. Finally, Notch-1, its ligands Delta-like-ligand 4 (DLL-4) and Jagged-1 (Jag-1) and downstream transcriptional repressors – Hey-1 and Hey-2 were quantified by Real-time PCR.

Results OSM alone significantly induced IL-6 and MCP-1 while inhibiting IL-8 and GROα in RASFC and HMVEC culture supernatants, compared to basal control. OSM alone induced RANTES expression in HMVEC with little effect observed for RASFC. OSM potentiated the effect of increasing concentrations of TNFα on IL-6 and MCP-1 secretion from RASFC and HMVEC. Conversely OSM significantly inhibited TNFα-induced IL-8 and GROα secretion from both RASFC and HMVEC. Interestingly, OSM significantly inhibited TNFa-induced RANTES expression in HMVEC yet conversely potentiated this effect in RASFC. At a functional level, OSM induced both RASFC and HMVEC invasion and induced network formation and VEGF expression in HMVEC. OSM significantly induced Notch-1 in RASFC and HMVEC in a time dependent manner, but interestingly differentially regulated the Notch-1 ligands, with induction of Jag-1 only observed in RASFC, and induction of DLL-4 only observed in HMVEC. Finally OSM differentially regulated Notch-1 downstream transcriptional repressors in HMVEC, significantly inducing Hey-2 while simultaneously inhibiting Hey-1.

Conclusions OSM is a pleiotropic cytokine that displays divergent effects with both pro- and anti-inflammatory mechanisms within the inflamed joint, effects that appear to be dependent on cell type and the inflammatory microenvironment. Targeting OSM or downstream signalling pathways may lead to new potential therapeutic strategies or adjuvant therapies, particularly for those patients who have sub-optimal responses.

Disclosure of Interest None declared

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