Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data (U133 Plus 2.0) from fibroblast like synoviocytes from patients with rheumatoid arthritis (RA-FLS) stimulated by TL1A

ABSTRACT: TNF-like ligand 1A (TL1A) is a member of TNF receptor superfamily and involved in the pathogenesis of autoimmune diseases by inducing apoptosis via intracellular death domain or promoting inflammation through the activation of NFM-NM-:B by binding to its specific receptor death receptor 3 (DR3). Meanwhile, decoy receptor 3 (DcR3) competitively binds soluble TL1A in addition to Fas-ligand (FasL) and LIGHT and inhibits the signaling of TL1A via DR3. DcR3 overexpressed in rheumatoid synovial fibroblasts (RA-FLS) stimulated with inflammatory cytokines such as TNFM-NM-1 or IL-1M-NM-2 inhibits Fas-induced apoptosis. In contrast, DcR3 inhibited cell proliferation induced by inflammatory cytokines via membrane-bound TL1A expressed on RA-FLS. Therefore, TL1A-DcR3/DR3 signaling may be involved in the pathogenesis of RA by modulating apoptosis and proliferation of RA-FLS. We hypothesized that TL1A regulates the gene expression in RA-FLS. We used to search for genes in which expression in RA-FLS is regulated by the ligation of TL1A. RA-FLS were obtained from 4 RA patients (sample1-4). Each sample was incubated with either 1.0 M-NM-

ORGANISM(S): Homo sapiens

SUBMITTER: Toshihisa Maeda

PROVIDER: E-GEOD-63995 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS

Project description:Inflammation-mediated oncogenesis has been implicated in a variety of cancer types. Rheumatoid synovial tissues can be viewed as a tumor-like mass, consisting of hyperplastic fibroblast-like synoviocytes (FLSs). FLSs of rheumatoid arthritis (RA) patients have pro-migratory and invasive characteristics, which may be caused by chronic exposure to genotoxic stimuli, including hypoxia and growth factors. We tested whether a transformed phenotype of RA-FLSs is associated with placental growth factor (PlGF), a representative angiogenic growth factor induced by hypoxia. Here, we identified PlGF-1 and PlGF-2 as the major PlGF isoforms in RA-FLSs. Global gene expression profiling revealed that cell proliferation, apoptosis, angiogenesis, and cell migration were mainly represented by differentially expressed genes in RA-FLSs transfected with siRNA for PlGF. Indeed, PlGF-deficient RA-FLSs showed a decrease in cell proliferation, migration, and invasion, but an increase in apoptotic death in vitro. PlGF gene overexpression resulted in the opposite effects. Moreover, exogeneous PlGF-1 and PlGF-2 increased survival, migration, and invasiveness of RA-FLSs by binding their receptors, Flt-1 and NP-1, up-regulating the expression of anti-apoptotic molecules, pErk and Bcl2. Knock-down of PlGF transcripts reduced RA-FLS proliferation in a xeno-transplantation model. Collectively, in addition to their role for neovascularization, PlGF-1 and -2 promote proliferation, survival, migration, and invasion of RA-FLSs in an autocrine and paracrine manner. These results demonstrated how primary cells of mesenchymal origin acquired an aggressive and transformed phenotype. PlGF and its receptors thus offer new targets for anti-FLS therapy. The FLSs were prepared from the synovial tissues of RA patients and incubated in DMEM supplemented with 10% FBS. Cells were cultured in RPMI supplemented with 10% FBS. There are 4 FLS samples treated with PlGF siRNA, and 4 FLS samples treated with control siRNA.

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Expression data (U133 Plus 2.0) from fibroblast like synoviocytes from patients with rheumatoid arthritis (RA-FLS) stimulated by TL1A

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