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, eve hypothesized that elevat ed 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 PGE(2). To test this hypothe sis, we first measured the levels of IL-17 and IL-15 using specific ELISA a nd found that synovial fluids of patients with rheumatoid arthritis, but no t with osteoarthritis, contain high levels of these cytokines, A strong cor relation between IL-15 and IL-17 levels in synovial fluids was observed. Am ong tested factors, LPS and TNF-alpha failed, IL-15 and IL-2 were equipoten t, and PMA + ionomycin was far more efficient in the induction of IL-17 sec retion by PBMCs isolated from healthy blood donors. Interestingly, synovial fluid cells, in contrast to PBMCs isolated from patients with rheumatoid a rthritis, but not osteoarthritis, respond to PMA + ionomycin with much lowe r, comparable to IL-15-triggered IL-17 secretion. Moreover, PMA + ionomycin -triggered IL-17 secretion is completely or partially blocked in the presen ce of low doses of cyclosporin A or high doses of methylprednisolone, respe ctively, 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 sensi tive pathways leads to the overproduction of IL-17 in the joints of rheumat oid arthritis patients.