Recent findings on phosphoinositide-3 kinase in rheumatic diseases

Abstract

Rheumatic diseases are chronic inflammatory disorders, and many of them are autoimmune diseases. Class I phosphatidylinositol-3 kinases (PI3Ks) are enzymes that phosphorylate phosphoinositides in response to extracellular stimuli and regulates cellular activation, proliferation, and migration, in a variety of cell types, suggesting that they play critical roles in the development of inflammation. In patients with rheumatic diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), recent reports have shown convincing pathogenic evidence for the involvement of PI3K/Akt signaling pathways in chronic inflammation. Moreover, selective inhibition of PI3K γ reduced incidence and severity of the renal disease. More recently, the kinome array analysis revealed particular up-regulation of PI3K in B cells from patients with SLE in comparison with matched controls. Up-regulation of PI3K in T cells was also reported in patients with SLE. Further, we have demonstrated anti-rheumatic effects of a novel PI3K-specific inhibitor, ZSTK474, in mouse collagen-induced arthritis (CIA). Administration of ZSTK474, even if started after the development of arthritis, ameliorated CIA with no apparent adverse effect. Proliferation of B lymphocytes and synovial fibroblasts were inhibited by ZSTK474 in vitro. ZSTK474 suppressed osteoclast formation in vitro and also in the joints of CIA mice. These findings indicate that PI3K might be a potential therapeutic target of rheumatic diseases.