Expression of interleukin‐18 and its monokine‐directed function in rheumatoid arthritis

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Abstract
Objectives. To investigate the expression of and monokine induction by interleukin 18 (IL‐18; also called interferon‐γ inducing factor, IGIF), in peripheral blood mononuclear cells (PBMC) and cultured synoviocytes from rheumatoid arthritis (RA) patients. Methods. We carried out IL‐18 Western blotting and semi‐quantitative reverse transcription–polymerase chain reaction (RT‐PCR) of cytokines in PBMC [IL‐18, IL‐1β and tumour necrosis factor α (TNF‐α)] and long‐term cultured fibroblast‐like synoviocytes (FLS) [IL‐18, IL‐1β, TNF‐α, IL‐6, interferon γ (INF‐γ) and [granulocyte–macrophage colony stimulating factor (GM‐CSF)] from RA patients and controls. FLS were isolated from RA synovial membranes (FLSSM) and RA synovial fluids (FLSSF), osteoarthritis (OA) FLSSM and FLSSF from spondyloarthropathy patients. FLS were characterized by fluorescence‐activated cell sorting of the FLS. PBMC and FLS from RA patients and control subjects were stimulated with recombinant human IL‐18 and IL‐1β (rHuIL‐18/rHuIL‐1β), and TNF‐α, IL‐1β and MMP‐1 were measured by ELISA in supernatants. Results. Constitutive expression of IL‐18 mRNA was significantly reduced whereas that of TNF‐α was enhanced in RA PBMC. Persistent low expression of IL‐18, TNF‐α, GM‐CSF and IL‐1β was observed in RA and OA FLSSM as well as spondyloarthropathy FLSSF. In contrast, high constitutive expression of IL‐18 in FLS (CD90/Thy‐1‐ and CD54‐positive, CD14‐ and CD86‐negative), accompanied by persistent high levels of TNF‐α, GM‐CSF and IL‐1β expression, was restricted to synovial fluid‐derived FLS obtained from RA patients. IFN‐γ was not detectable in any culture, but IL‐6 mRNA was equally expressed in all FLS cultures. rHuIL‐18 was effective in stimulating TNF‐α and IL‐1β secretion in PBMC from healthy controls, but failed to stimulate TNF‐α and IL‐1β secretion from PBMC in 11 of 12 RA patients, and all FLS cultures. rHu‐IL‐1β, but not rHu‐IL‐18, induced interstitial collagenase (MMP‐1) in FLS. Conclusions. Persistent high production of proinflammatory cytokines in RA‐FLSSF may be relevant for chronic progression in RA synovitis. Levels of TNF‐α and IL‐1β expression are increased in RA‐FLSSF, but are independent of IL‐18. The pathological function of enhanced IL‐18 expression in RA‐FLSSF remains to be further elucidated.

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