gms | German Medical Science

Background: Blocking individual cytokines or cytokine receptors by biologics has proven great efficacy in the treatment of rheumatoid arthritis (RA). However, sustained remission is rarely achieved. Due to their capacity to block the intracellular signalling of several cytokines at the same time, janus kinase inhibitors (JAKi) have shown to be an efficient therapeutic option in RA treatment. Crosstalk between infiltrating lymphocytes and synovial fibroblasts (SF) is suggested to contribute to an amplification of inflammatory signals as well as the chronicity of the disease. However, SF also possess immunosuppressive capacities. As we have shown before, SF strongly suppress the proliferation and cytokine expression of activated lymphocytes. The aim of this study was to examine the effects of JAKi and biologics used in RA therapy on the cross-talk between lymphocytes and SF, particularly on the pro-inflammatory versus immunosuppressive properties of SF.

Methods: SF were stimulated with conditioned media of activated B or T cells of normal healthy donors or RA patients in the presence of JAKi or biologics. Secretion of pro-inflammatory cytokines and matrix metalloproteinases (MMP) were quantified by ELISA. Glucose metabolism was analysed by quantifying glucose and lactate levels using NMR spectroscopy. Furthermore, the influence of JAKi and biologics on the T cell-suppressive functions of SF was investigated by co-culturing Th cells with SF and analysis of T cell proliferation by flow cytometry and IDO1 expression by western blot.

Results: Stimulation with activated lymphocytes resulted in strong induction of interleukin (IL)-6, IL-8, and MMP3 expression by SF. Adalimumab, Canakinumab, and most efficiently Secukinumab, but not Tocilizumab, significantly reduced secretion of these cytokines. Similar to Secukinumab, strong inhibition was achieved by the JAKi Baricitinib and Tofacitinib. In contrast, only JAKi significantly attenuated the expression of hexokinase 2 and aerobic glycolysis induced by activated lymphocytes. Furthermore, the activation of chronically stimulated SF was inhibited by JAKi. Moreover, JAKi significantly reduced IDO1 expression and suppression of T cell proliferation by SF, whereas biologics showed no effect.

Conclusion: JAKi efficiently suppress the pro-inflammatory response of SF induced by activated lymphocytes. However, in contrast to biologics, JAKi also reduce the immunosuppressive properties of SF.