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

Abstract

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). 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. 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. 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.