Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still's disease

Objective. Interleukin-18 (IL-18) is a proinflammatory cytokine that is inv olved in immunologically mediated tissue damage, but its bioactivity is reg ulated in vivo by its soluble decoy receptor, IL-18 binding protein (IL-18B P). This study was undertaken to determine levels of IL-18 and IL-18 bindin g inhibition in the blood of patients with adult-onset Still's disease (ASD ). Methods. Serum concentrations of IL-18 in ASD patients were compared by enz yme-linked immunosorbent assay (ELISA) with those in patients with other sy stemic rheumatic diseases and healthy controls. The biologically active mat ure protein of IL-18 was detected by Western blot analysis with anti-IL-18 antibody and its induction of interferon-gamma (IFN gamma) secretion from I L-18-responding human myelomonocytic KG-1 cells. The inhibitory activity on IL-18 binding to its receptor was determined by I-125-IL-18 binding inhibi tion assay using the Chinese hamster ovary cell line transfected with a mur ine IL-18 receptor (CHO-K1/mIL-18R). Results. Concentrations of serum IL-18 were extremely elevated in patients with active ASD compared with those in patients with rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, polymyositis/dermatomyosi tis, Sjogren's syndrome, or healthy individuals. Levels of IL-18 were found to correlate with serum ferritin values and disease severity in ASD. Weste rn blot analysis revealed that serum samples from patients with active ASD contained an 18-kd polypeptide of IL-18, corresponding in size to the matur e form. Accordingly, the samples were able to induce IFN gamma secretion fr om KG-l cells, which was largely abolished by neutralizing anti-IL-18 antib ody. However, the level of IL-18 bioactivity was more than 10-fold weaker t han the concentration of IL-18 protein measured by ELISA. Serum samples fro m patients with active ASD showed an inhibitory effect on the binding of I- 125-IL-18 to CHO-K1/mIL-18R cells, and this activity was associated with el evation of IL-18. Conclusion. These data indicate that systemic overproduction of IL-18 may b e closely related to the pathogenesis of ASD, despite the restriction on it s inflammatory activity by IL-18 binding inhibitors such as IL-18BP. The di sease activity appears to be determined on the basis of the relative levels of IL-18 and its specific inhibitors.