Jak and Syk: Emerging their relevance to the treatment of inflammatory diseases

Abstract

The multiple soluble ligands such as cytokines play a pivotal role in the pathogenesis of inflammatory diseases. The appropriate intracellular signaling pathways must be activated via cytokine receptors on the cell surface and the tyrosine kinase transduce the first “outside to in” signals to be phosphorylated following receptor binding to its ligand. Among them, members of Janus kinase (Jak) family and Spleen tyrosine kinase (Syk) family are essential for the signaling pathways of various cytokines and are implicated in the pathogenesis of rheumatoid arthritis (RA), a representative autoimmune inflammatory disease. Selective inhibition of Jak3 was considered as a potential target in the treatment of RA and an orally available Jak3 inhibitor CP-690,550 (tofacitinib), is currently in clinical trials for RA with satisfactory effects and acceptable safety. Our in vitro experiments have indicated that the inhibition could be mediated through the suppression of IL-17 and IFN-γ production and proliferation of CD4⁺ T cells without directly affecting synovial fibroblasts and monocytes. Multiple global clinical examinations indicate that JAK inhibition with CP-690,550 in patients with RA results in rapid and remarkable clinical effects without severe adverse events. A selective Syk inhibitor R788 (fostamatinib) has been shown to be effective for the treatment of not only RA but also bronchial asthma, B-cell lymphoma and idiopathic thrombocytopenic purpura. We have found that Syk-mediated B cell receptor (BCR)-signaling is prerequisite for optimal induction of toll-like receptor (TLR)-9, thereby allowing efficient propagation of CD40 and TLR9-signaling in human B cells. These results indicate that inhibition of Syk have a potential to regulate B-cell mediated inflammatory diseases such as systemic lupus etythematosus (SLE). We here document the in vitro and in vivo effects of a Jak inhibitor and a Syk inhibitor for the treatment of autoimmune inflammatory diseases, mainly RA and SLE.