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 involved in immunologically mediated tissue damage, but its bioactivity is regulated in vivo by its soluble decoy receptor, IL-18 binding protein (IL-18BP). This study was undertaken to determine levels of IL-18 and IL-18 binding 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 enzyme-linked immunosorbent assay (ELISA) with those in patients with other systemic rheumatic diseases and healthy controls. The biologically active mature protein of IL-18 was detected by Western blot analysis with anti-IL-18 antibody and its induction of interferon-gamma (IFNgamma) secretion from IL-18-responding human myelomonocytic KG-1 cells. The inhibitory activity on IL-18 binding to its receptor was determined by 125I-IL-18 binding inhibition assay using the Chinese hamster ovary cell line transfected with a murine 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/dermatomyositis, Sjogren's syndrome, or healthy individuals. Levels of IL-18 were found to correlate with serum ferritin values and disease severity in ASD. Western blot analysis revealed that serum samples from patients with active ASD contained an 18-kd polypeptide of IL-18, corresponding in size to the mature form. Accordingly, the samples were able to induce IFNgamma secretion from KG-1 cells, which was largely abolished by neutralizing anti-IL-18 antibody. However, the level of IL-18 bioactivity was more than 10-fold weaker than the concentration of IL-18 protein measured by ELISA. Serum samples from patients with active ASD showed an inhibitory effect on the binding of 125I-IL-18 to CHO-K1/mIL-18R cells, and this activity was associated with elevation of IL-18.


CONCLUSIONS
These data indicate that systemic overproduction of IL-18 may be closely related to the pathogenesis of ASD, despite the restriction on its inflammatory activity by IL-18 binding inhibitors such as IL-18BP. The disease activity appears to be determined on the basis of the relative levels of IL-18 and its specific inhibitors.
Okayama University Medical School, Japan.
M
M
Kawashima
M
M
Yamamura
M
M
Taniai
H
H
Yamauchi
T
T
Tanimoto
M
M
Kurimoto
S
S
Miyawaki
T
T
Amano
T
T
Takeuchi
H
H
Makino
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood; D001775:Blood Circulation; D005260:Female; D015870:Gene Expression; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000097:blood*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000097:blood / Q000235:genetics; D008297:Male; D009000:Monocytes / Q000737:chemistry; D012333:RNA, Messenger / Q000097:blood; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016706:Still's Disease, Adult-Onset / Q000097:blood*
D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D012333:RNA, Messenger; C118370:interleukin-18 binding protein