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Am J Pathol ; 187(1): 156-162, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27865758

ABSTRACT

IL-34 is a proinflammatory cytokine implicated in rheumatoid arthritis (RA). The current study aimed to assess the IL-34 expression in response to two members of the transforming growth factor (TGF)-ß family, TGF-ß1 and bone morphogenetic protein (BMP)-2, in synovial fibroblasts from RA patients. IL-34, TGF-ß1, and BMP-2 productions were measured in patient synovial fluids by enzyme-linked immunosorbent assay. IL-34 mRNA levels were quantified by real-time quantitative PCR in human synovial fibroblasts and murine mesenchymal stem cells. Pharmacologic inhibitions were used to determine the involvement of activin receptor-like kinase 1 (ALK1) and ALK5 downstream TGF-ß1 and BMP-2. IL-34, TGF-ß1, and BMP-2 were expressed in synovial fluids from RA patients. We found a significant correlation between IL-34 and TGF-ß1 expressions. Levels of both IL-34 and TGF-ß1 were thus correlated with the total leukocyte counts in the synovial fluids. TGF-ß1 and BMP-2 decreased IL-34 expression in the synovial fibroblasts or in murine mesenchymal stem cells in a dose- and time-dependent manner through ALK5 and ALK1 pathways, respectively. In addition, TGF-ß1 and BMP-2 antagonized tumor necrosis factor α-induced IL-34 gene expression. This work identifies TGF-ß1 and BMP-2 as potent inhibitors of IL-34 expression in RA synovial fibroblasts. These cytokines, as upstream inhibitors of IL-34, may thus contribute to antagonize inflammation and bone erosions in RA.


Subject(s)
Arthritis, Rheumatoid/pathology , Bone Morphogenetic Protein 2/metabolism , Fibroblasts/metabolism , Inflammation/pathology , Interleukins/metabolism , Synovial Membrane/pathology , Transforming Growth Factor beta1/metabolism , Activin Receptors, Type II/metabolism , Adult , Aged , Aged, 80 and over , Animals , Female , Fibroblasts/pathology , Humans , Male , Mesenchymal Stem Cells/metabolism , Mice , Middle Aged , Models, Biological , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism
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