The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels
Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT factors.
This study examined the expression and phosphorylation of STAT1 and STAT3 in unstimulated T cells and monocytes, and their activation by cytokines IFN-g, IL-6 and IL-10, using real-time PCR and multicolour flow cytometric analysis on samples from patients with active RA.
The results of the study show that; expression and phosphorylation of STAT3 are elevated in circulating T cells and monocytes in RA; baseline activation of STAT3 in RA correlates with IL-6 levels; a proportion of RA T cells are hyporesponsive to IL-6-mediated STAT3 activation in vitro. These finding suggest that a synthetic inhibitor that would specifically target the IL-6/STAT3 signalling pathway might have beneficial therapeutic characteristics in RA.