Up-regulation of stromal cell-derived factor 1 (CXCL12) production in rheumatoid synovial fibroblasts through interactions with T lymphocytes: role of interleukin-17 and CD40L-CD40 interaction

Arthritis Rheum. 2007 Apr;56(4):1076-86. doi: 10.1002/art.22439.


Objective: Stromal cell-derived factor 1 (SDF-1) is a potent chemoattractant for memory T cells in inflamed rheumatoid arthritis (RA) synovium. This study was undertaken to investigate the effect of interleukin-17 (IL-17) and CD40-CD40L interaction on SDF-1 production in RA fibroblast-like synoviocytes (FLS).

Methods: Synovial fluid (SF) and serum levels of SDF-1 in RA patients were measured by enzyme-linked immunosorbent assay (ELISA). The SDF-1 produced by cultured RA FLS was evaluated by real-time polymerase chain reaction and ELISA after FLS were treated with IL-17 and inhibitors of intracellular signal molecules. The SDF-1 level was also determined after FLS were cocultured with T cells in the presence and absence of IL-17.

Results: Concentrations of SDF-1 in the sera and SF were higher in RA patients than in osteoarthritis patients, although the increase in the serum levels did not reach statistical significance. The production of SDF-1 in RA FLS was enhanced by IL-17 stimulation. This effect of IL-17 was blocked by inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), NF-kappaB, and activator protein 1 (AP-1). When FLS were cocultured with T cells, SDF-1 production was up-regulated, especially in the presence of IL-17, but FLS were inhibited by neutralizing anti-IL-17 and anti-CD40L antibodies. Addition of RA SF to cultured RA FLS significantly up-regulated SDF-1 messenger RNA expression, which was hampered by pretreatment with anti-IL-17 antibody.

Conclusion: SDF-1 is overproduced in RA FLS, and IL-17 could up-regulate the expression of SDF-1 in RA FLS via pathways mediated by PI 3-kinase, NF-kappaB, and AP-1. Our findings suggest that inhibition of the interaction between IL-17 from T cells and SDF-1 in FLS may provide a new therapeutic approach in RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Blocking / pharmacology
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism*
  • CD4-Positive T-Lymphocytes / pathology
  • CD40 Antigens / metabolism
  • CD40 Ligand / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemokine CXCL12
  • Chemokines, CXC / genetics
  • Chemokines, CXC / metabolism*
  • Coculture Techniques
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Interleukin-17 / immunology
  • Interleukin-17 / metabolism
  • Interleukin-17 / pharmacology
  • Middle Aged
  • Stromal Cells / metabolism*
  • Synovial Fluid / cytology
  • Synovial Fluid / metabolism*
  • Up-Regulation


  • Antibodies, Blocking
  • CD40 Antigens
  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Interleukin-17
  • CD40 Ligand