High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism.
Recent data suggest that IL-15 plays an important role in the pathogenesis of rheumatoid arthritis. In the present study, we hypothesized that elevated in the joints of rheumatoid arthritis, but not osteoarthritis, patients, IL-15 may exert its proinflammatory properties via the induction of IL-17, a cytokine known to stimulate synoviocytes to release several mediators of inflammation including IL-6, IL-8, GM-CSF and PGE2. To test this hypothesis, we first measured the levels of IL-17 and IL-15 using specific ELISA and found that synovial fluids of patients with rheumatoid arthritis, but not with osteoarthritis, contain high levels of these cytokines. A strong correlation between IL-15 and IL-17 levels in synovial fluids was observed. Among tested factors, LPS and TNF-alpha failed, IL-15 and IL-2 were equipotent, and PMA + ionomycin was far more efficient in the induction of IL-17 secretion by PBMCs isolated from healthy blood donors. Interestingly, synovial fluid cells, in contrast to PBMCs isolated from patients with rheumatoid arthritis, but not osteoarthritis, respond to PMA + ionomycin with much lower, comparable to IL-15-triggered IL-17 secretion. Moreover, PMA + ionomycin-triggered IL-17 secretion is completely or partially blocked in the presence of low doses of cyclosporin A or high doses of methylprednisolone, respectively. IL-15-triggered IL-17 secretion by PBMCs was completely inhibited by these drugs. Thus, our results suggest for the first time that IL-15 may represent a physiological trigger that via cyclosporin A and steroid sensitive pathways leads to the overproduction of IL-17 in the joints of rheumatoid arthritis patients.
Ziolkowska
M
M
Departments ofPathophysiology and Immunology, Rehabilitation, and Connective Tissue Disease, Institute of Rheumatology, Warsaw, Poland.
Koc
A
A
Luszczykiewicz
G
G
Ksiezopolska-Pietrzak
K
K
Klimczak
E
E
Chwalinska-Sadowska
H
H
Maslinski
W
W
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000097:blood; D007376:Interleukin-2 / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008775:Methylprednisolone / Q000494:pharmacology; D008875:Middle Aged; D010003:Osteoarthritis / Q000097:blood / Q000276:immunology / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology; D013582:Synovial Fluid / Q000276:immunology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D019409:Interleukin-15; D020381:Interleukin-17; D007376:Interleukin-2; D010835:Phytohemagglutinins; D015759:Ionomycin; D016572:Cyclosporine; D013755:Tetradecanoylphorbol Acetate; D008775:Methylprednisolone