PI3 Kinase δ Is a Key Regulator of Synoviocyte Function in Rheumatoid Arthritis

Class I phosphoinositide 3 kinase (PI3K) delta is a promising therapeutic target for rheumatoid arthritis (RA) because of its contribution to leukocyte biology. However, its contribution in fibroblasts has not been studied as a mechanism that contributes to efficacy. We investigated the expression and function of PI3K delta in synovium and cultured fibroblast-like synoviocytes (FLS). Inununohistochemistry demonstrated that PI3K delta is highly expressed in RA synovium, especially in the synovial lining. Using quantitative PCR and Western blot analysis, we found that PI3K delta mRNA and protein expression is higher in RA than in osteoarthritis (OA) synovium. PI3K delta was also expressed in cultured FLS, along with PI3K alpha and PI3K beta, whereas PI3K gamma was not detectable. PI3K delta mRNA expression was selectively induced by inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) but not by growth factors platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta). The use of inhibitors that block individual PI3K isoforms, including the novel selective PI3K delta inhibitor INK007, showed that PI3K delta is required for PDGF- and TNF-induced Akt activation. PI3K delta inhibition also diminished PDGF-mediated synoviocyte growth and sensitized cells to H2O2-induced apoptosis. These data are the first documentation of increased PI3K delta expression in both RA synovium and cultured synoviocytes. Furthermore, these are the first data demonstrating that PI3K delta is a major regulator of PDGF-mediated fibroblast growth and survival via Akt. Thus, targeting PI3K delta in RA could modulate synoviocyte function via anti-inflammatory and disease-altering mechanisms. (Am J Pathol 2012, 180:1906-1916; DOI: 10.1016/j.ajpath.2012.01.030)