A mechanism of IL-17 action in the rheumatoid arthritis

Abstract

Interleukin (IL) -17 is a newly discovered T cell-derived cytokine whose role in osteoclast development has not been fully elucidated. Treatment of co-cultures of mouse hemopoietic cells and primary osteoblastic cells with recombinant human IL-17 induced the formation of multinucleated cells, which satisfied major criteria of osteoclasts such as tartrate-resistant acid phosphatase (TRAP) activity, calcitonin receptors, and pit formation on dentine slices. Direct interaction between osteoclast progenitors and osteoblasts was required for osteoclastogenesis induced by IL-17, which was completely inhibited by adding indomethacin or NS 398, a selective inhibitor of cyclooxgenase-2 (COX-2) . Adding IL-17 increased prostaglandin E2 (PGE2) synthesis both in co-cultures of bone marrow cells and osteoblastic cells and in single cultures of osteoblastic cells, but not in single cultures of bone marrow cells. In addition, IL-17 dose-dependently induced expression of osteoclast differentiation factor (ODF) mRNA in osteoblastic cells. ODF is a membrane-associated protein, which transduces an essential signal (s) to osteoclast progenitors for differentiation into osteoclasts. Osteoclastogenesis inhibitory factor (OCIF), a decoy receptor of ODF, completely inhibited IL-17-induced osteoclast differentiation in the co-cultures. Levels of IL-17 in synovial fluids were significantly higher in rheumatoid arthritis (RA) patients than osteoarthritis (OA) patients (p<0.0001) . Anti-IL-17 antibody significantly inhibited OCL formation in the co-cultures with culture media of RA synovial tissues. These findings suggest that IL-17 first acts on osteoblastic cells, which stimulates both COX-2-dependent PGE2 synthesis and ODF gene expression, which in turn induce differentiation of osteoclast progenitors into mature osteoclasts. IL-17 may be involved in osteoclastic bone resorption in RA patients. It has been reported that IL-17 also produce many factors inducing degradation cartilage in RA. Therefore, IL-17 may play a pivotal role in joint destruction in RA.