EXTENDED REPORT

Interleukin (IL) 18 stimulates osteoclast formation through synovial T cells in rheumatoid arthritis: comparison with IL1ß and tumour necrosis factor

S-M Dai^1,2, K Nishioka¹, K Yudoh¹

¹ Department of Bioregulation, Institute of Medical Science, St Marianna University School of Medicine, Kawasaki, Japan
² Department of Rheumatology and Immunology, Changhai Hospital, Second Military Medical University, Shanghai, China

Correspondence to:
Correspondence to:
Dr K Yudoh
Department of Bioregulation, Institute of Medical Science, St Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8512, Japan; yudo{at}marianna-u.ac.jp

Objective: To determine whether IL18 has any indirect effects on osteoclastogenesis mediated by T cells in RA synovium, and compare its effects with those of IL1ß and TNF.

Methods: Resting T cells were isolated from peripheral blood of healthy donors, and stimulated with 2 µg/ml phytohaemagglutinin (PHA) and 0.5 ng/ml IL2 for 24 hours. Synovial T cells were isolated from RA synovial tissue. The levels of soluble receptor activator of the NF-B ligand (RANKL), osteoprotegerin (OPG), IFN, M-CSF, and GM-CSF were determined by ELISA. Membrane bound RANKL expression was analysed by flow cytometry. Commercially available human osteoclast precursors were cocultured with T cells to induce osteoclast formation, which was determined with tartrate resistant acid phosphatase staining and pit formation assay.

Results: In PHA prestimulated T cells or RA synovial T cells, IL18, IL1ß, or TNF increased soluble RANKL production and membrane bound RANKL expression in a dose dependent manner. IL18, IL1ß, and TNF did not induce M-CSF, GM-CSF, IFN, or OPG production in PHA prestimulated T cells or RA synovial T cells. IL18 increased the number of osteoclasts and bone resorption area on dentine slices in the coculture of human osteoclast precursors with PHA prestimulated T cells or RA synovial T cells; its ability was equivalent to that of IL1ß, but less potent than that of TNF. In the coculture system, OPG completely blocked osteoclast induction by IL18 or IL1ß, and greatly inhibited induction by TNF.

Conclusion: IL18, IL1ß, or TNF can indirectly stimulate osteoclast formation through up regulation of RANKL production from T cells in RA synovitis; IL18 is as effective as IL1ß, but less potent than TNF.

Abbreviations: ELISA, enzyme linked immunosorbent assay; FCS, fetal calf serum; GM-CSF, granulocyte monocyte-colony stimulating factor; IFN, interferon ; IL, interleukin; M-CSF, monocyte/macrophage-colony stimulating factor; -MEM, -minimal essential medium; MFI, mean fluorescence intensity; OPG, osteoprotegerin; PBS, phosphate buffered saline; PHA, phytohaemagglutinin; RA, rheumatoid arthritis; RANK, receptor activator of NF-B; RANKL, receptor activator of NF-B ligand; TNF, tumour necrosis factor ; TRAP, tartrate resistant acid phosphatase

Keywords: interleukin 18; interleukin 1ß; tumour necrosis factor ; osteoclasts; rheumatoid arthritis

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