Interleukin-21 induces migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis

Clin Exp Immunol. 2016 May;184(2):147-58. doi: 10.1111/cei.12751. Epub 2016 Feb 15.

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone erosion. Fibroblast-like synoviocytes (FLS) play a pivotal role in RA pathogenesis through aggressive migration and matrix invasion, and certain proinflammatory cytokines may affect synoviocyte invasion. Whether interleukin (IL)-21 influences this process remains controversial. Here, we evaluated the potential regulatory effect of IL-21 on the migration, invasion and matrix metalloproteinase (MMP) expression in RA-FLS. We found that IL-21 promoted the migration, invasion and MMP (MMP-2, MMP-3, MMP-9, MMP-13) production in RA-FLS. Moreover, IL-21 induced activation of the phosphoinositide 3-kinase (PI3K), signal transducer and activator of transcription-3 (STAT-3) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) pathways, and blockage of these pathways [PI3K/protein kinase B (AKT) inhibitor LY294002, STAT-3 inhibitor STA-21 and ERK1/2 inhibitor PD98059] attenuated IL-21-induced migration and secretion of MMP-3 and MMP-9. In conclusion, our results suggest that IL-21 promotes migration and invasion of RA-FLS. Therefore, therapeutic strategies targeting IL-21 might be effective for the treatment of RA.

Keywords: fibroblast-like synoviocytes; interleukin-21; invasion; matrix metalloproteinases; migration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Arthritis, Rheumatoid / immunology*
  • CD4-Positive T-Lymphocytes / immunology
  • Cadherins / biosynthesis
  • Cell Movement / drug effects*
  • Cells, Cultured
  • Chromones / pharmacology
  • Enzyme Activation / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Fibroblasts / metabolism
  • Flavonoids / pharmacology
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Interleukin-21
  • Interleukins / immunology
  • Interleukins / pharmacology*
  • Killer Cells, Natural / immunology
  • Matrix Metalloproteinase 13 / biosynthesis
  • Matrix Metalloproteinase 2 / biosynthesis
  • Matrix Metalloproteinase 3 / biosynthesis
  • Matrix Metalloproteinase 9 / biosynthesis
  • Middle Aged
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Polycyclic Compounds / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / antagonists & inhibitors
  • STAT3 Transcription Factor / metabolism
  • Synovial Membrane / cytology*
  • Synovial Membrane / metabolism

Substances

  • Cadherins
  • Chromones
  • Flavonoids
  • ICAM1 protein, human
  • Interleukins
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Polycyclic Compounds
  • STA-21
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Intercellular Adhesion Molecule-1
  • osteoblast cadherin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Extracellular Signal-Regulated MAP Kinases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • MMP3 protein, human
  • Matrix Metalloproteinase 3
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • MMP9 protein, human
  • Matrix Metalloproteinase 9
  • Interleukin-21
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one