Hypoxia and STAT3 signalling interactions regulate pro-inflammatory pathways in rheumatoid arthritis
Hypoxia is a key driving force in joint inflammation, however little is known about the effect it can have on JAK/STAT signalling in rheumatoid arthritis. Due to the development of JAK inhibitors as therapeutics it is important to understand any links there may be. Previous studies have shown that HIF1a, a protein associated with hypoxia, facilitates the binding of STAT3 to haptoglobin promoter in HepG2 human hepatoma cells. HIF1a also requires interaction of Notch signalling pathways with STAT3 for transcription. Notch-1, with its associated ligands and downstream target genes, is expressed in inflamed synovium and inversely associated with p02. Hypoxia induced p-STAT3, p-STAT1 and HIF1a were blocked with the addition of Stat3-siRNA and WP1066, a JAK2 inhibitor. Cell invasion, migration and cytokine production, all hypoxia induced, were also inhibited. These results demonstrate the evidence of a functional link between HIF1a, STAT3 and Notch-1 signalling in the regulation of proinflammatory mechanisms in RA; this is the first paper to demonstrate that link.