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.
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.


CONCLUSIONS
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.
Kim
Kyoung-Woon
KW
Catholic University of Korea, and Department of Internal Medicine, Konkuk University Hospital, Seoul, Korea.
Cho
Mi-La
ML
Kim
Hae-Rim
HR
Ju
Ji-Hyeon
JH
Park
Mi-Kyung
MK
Oh
Hye-Jwa
HJ
Kim
Joon-Seok
JS
Park
Sung-Hwan
SH
Lee
Sang-Heon
SH
Kim
Ho-Youn
HY
D000328:Adult; D000368:Aged; D019138:Antibodies, Blocking / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008875:Middle Aged; D017154:Stromal Cells / Q000378:metabolism*; D013582:Synovial Fluid / Q000166:cytology / Q000378:metabolism*; D015854:Up-Regulation
D019138:Antibodies, Blocking; D019013:CD40 Antigens; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D020381:Interleukin-17; D023201:CD40 Ligand