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

• DOI: 10.1016/j.ajpath.2012.01.030
• Publication Date: 2012-03-17T12:37:10Z
• Authors: Beatrix Bartok; David L. Boyle; Yi Liu; Pingda Ren; Scott T. Ball; William D. Bugbee; Christian Rommel; Gary S. Firestein
• Keywords: Platelet-Derived Growth Factor; 0303 health sciences; Cell Survival; Class I Phosphatidylinositol 3-Kinases; Synovial Membrane; Apoptosis; Fibroblasts; Gene Expression Regulation, Enzymologic; 3. Good health; Arthritis, Rheumatoid; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Transforming Growth Factor beta; Osteoarthritis; Cytokines; Humans; RNA, Messenger; Enzyme Inhibitors; Inflammation Mediators; Proto-Oncogene Proteins c-akt; Cell Division; Cells, Cultured; Phosphoinositide-3 Kinase Inhibitors

Class I phosphoinositide 3 kinase (PI3K) δ 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 PI3Kδ in synovium and cultured fibroblast-like synoviocytes (FLS). Immunohistochemistry demonstrated that PI3Kδ is highly expressed in RA synovium, especially in the synovial lining. Using quantitative PCR and Western blot analysis, we found that PI3Kδ mRNA and protein expression is higher in RA than in osteoarthritis (OA) synovium. PI3Kδ was also expressed in cultured FLS, along with PI3Kα and PI3Kβ, whereas PI3Kγ was not detectable. PI3Kδ 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 β (TGFβ). The use of inhibitors that block individual PI3K isoforms, including the novel selective PI3Kδ inhibitor INK007, showed that PI3Kδ is required for PDGF- and TNF-induced Akt activation. PI3Kδ inhibition also diminished PDGF-mediated synoviocyte growth and sensitized cells to H(2)O(2)-induced apoptosis. These data are the first documentation of increased PI3Kδ expression in both RA synovium and cultured synoviocytes. Furthermore, these are the first data demonstrating that PI3Kδ is a major regulator of PDGF-mediated fibroblast growth and survival via Akt. Thus, targeting PI3Kδ in RA could modulate synoviocyte function via anti-inflammatory and disease-altering mechanisms.