Furthermore sustained hypoxia activates NF-kB dependent gene expression, which is a key regulator of inflammation genes. Together this data highlights the ability of hypoxia to regulate diverse signalling pathways that are involved in the pro-inflammatory response. In this study we demonstrate that IL-17A is expressed by important immune cells including mast cells U0126 MEK inhibitor within the inflamed synovium. Furthermore, we demonstrate a relationship between in vivo measures of hypoxia and IL-17A producing cells in the inflamed joint; however it is unclear whether this effect is direct or indirect. In this study we demonstrate in vivo the presence of IL-17A expressing -neutrophils, mast cells and T–cells within the inflamed synovium. Percentage positivity of IL-17A was highest on neutrophils, followed by mast cells and then CD4+T cells. We demonstrate that IL-17A is highly expressed in the inflamed joint and is associated with the expression of IL-6 and inflammatory cell infiltrate. Furthermore, we demonstrate tissue mononuclear cell expression of IL-17A is significantly higher in patients with low in vivo tissue pO2 levels. Finally no difference in IL-17A levels was observed following exposure to hypoxia in vitro. Expression of IL-17A on CD15+neutrophils and tryptase+ mast cells in addition to CD4+T-cells further supports the concept that IL-17A plays a key role in the pathogenesis of inflammatory arthritis. This association with hypoxia, is most likely an indirect effect due to induced infiltration of inflammatory immune cells into the synovial pannus. IL-17A expression is significantly higher in inflammatory arthritis SF compared to serum levels, suggesting IL-17A production is predominantly localized within the joint consistent with our previous findings. Furthermore, IL-17A expression within the joint has been shown to strongly correlate with disease activity and inflammation. Immunohistochemical analysis of ST from inflammatory arthritis patients demonstrated sublining expression of IL-17A, particularly in areas of lymphoid infiltration. In previous reports these cells were mainly mononuclear although we now demonstrate, IL-17A+ synovial PMN cells colocalizing IL-17A with tryptase+ mast cells and CD15+ neutrophils. Murine mast cells and neutrophils have been previously shown to express IL-17A following specific stimulation; however, it has not been well established in human tissue. Furthermore, these cells have are known to be a key source of proinflammatory cytokines in human RA ST, and interact with RA synovial fibroblast cells via the production of soluble mediators to enhance IL-6 secretion. Here we demonstrate mast cells and neutrophils expressing IL-17A within the inflamed synovium. Both cell types have been implicated in the pathogenesis of CIA and other models of experimental arthritis. Our data supports Hueber et al, who demonstrated the majority of IL-17A expressing cells in RA synovial tissue were colocalised to mast cell. Furthermore they showed that proinflammatory stimuli such as TNFa.