Bone Morphogenetic Protein 2 and Transforming Growth Factor β1 Inhibit the Expression of the Proinflammatory Cytokine IL-34 in Rheumatoid Arthritis Synovial Fibroblasts

Am J Pathol. 2017 Jan;187(1):156-162. doi: 10.1016/j.ajpath.2016.09.015. Epub 2016 Nov 17.

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)-β family, TGF-β1 and bone morphogenetic protein (BMP)-2, in synovial fibroblasts from RA patients. IL-34, TGF-β1, 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-β1 and BMP-2. IL-34, TGF-β1, and BMP-2 were expressed in synovial fluids from RA patients. We found a significant correlation between IL-34 and TGF-β1 expressions. Levels of both IL-34 and TGF-β1 were thus correlated with the total leukocyte counts in the synovial fluids. TGF-β1 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-β1 and BMP-2 antagonized tumor necrosis factor α-induced IL-34 gene expression. This work identifies TGF-β1 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.

MeSH terms

  • Activin Receptors, Type II / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Arthritis, Rheumatoid / pathology*
  • Bone Morphogenetic Protein 2 / metabolism*
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Inflammation / pathology*
  • Interleukins / metabolism*
  • 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
  • Synovial Membrane / pathology*
  • Transforming Growth Factor beta1 / metabolism*

Substances

  • Bone Morphogenetic Protein 2
  • Interleukins
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • interleukin-34, human
  • interleukin-34, mouse
  • Protein-Serine-Threonine Kinases
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • Receptor, Transforming Growth Factor-beta Type I
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse