Introduction Oncostatin M (OSM) is a pleiotropic cytokine that has both agonistic and antagonistic effects depending on the inflammatory microenvironment. This study examines the effect of OSM on TNFα-induced pro-inflammatory mechanisms and on Notch-1 signalling in Rheumatoid Arthritis.
Methods Primary RA synovial fibroblasts (RASFC) isolated from RA synovial biopsiesobtained at time of knee arthroscopy and human dermal microvascular endothelial cells (HMVEC) were grown to confluence. RASFC and HMVEC were cultured with OSM (10ng/ml) 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 RASFC invasion were assessed by matrigel tube formation and Transwell invasions assays, VEGF in cell lysates by Real-time PCR. Finally, Notch-1, its ligands Delta-like-ligand 4 (DLL4)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. OSM alone induced RANTES expression in HMVEC with no effect observed for RASFC. OSM potentiated the effect of TNFα on IL-6 and MCP-1 secretion from RASFC and HMVEC. Conversely OSM inhibited TNFα-induced-IL-8 and GROα secretion from RASFC and HMVEC. Interestingly, OSM significantly inhibited TNFa-induced RANTES expression in HMVEC and conversely potentiated this effect in RASFC. At a functional level, OSM induced RASFC and HMVEC invasion and network formation and induced VEGF expression compared to basal control. Finally OSM significantly induced Notch-1 and Hey-2 in RASFC and HMVEC, 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.
Conclusion OSM is a pleiotrophic cytokine that differentiallyregulates pro-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 have therapeutic potential.
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