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

Abstract

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.

CONCLUSION:

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.

• Authors: M Kawashima, M Yamamura, M Taniai, H Yamauchi, T Tanimoto, M Kurimoto, S Miyawaki, T Amano, T Takeuchi, H Makino
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 44 Issue 3 Pg. 550-60 (Mar 2001) ISSN: 0004-3591 [Print] United States
• PMID: 11263769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glycoproteins
• Intercellular Signaling Peptides and Proteins
• Interleukin-18
• RNA, Messenger
• interleukin-18 binding protein

Topics

• Adult
• Arthritis, Rheumatoid (blood)
• Blood Circulation
• Female
• Gene Expression
• Glycoproteins (antagonists & inhibitors, blood)
• Humans
• Intercellular Signaling Peptides and Proteins
• Interleukin-18 (blood, genetics)
• Male
• Monocytes (chemistry)
• RNA, Messenger (blood)
• Reverse Transcriptase Polymerase Chain Reaction
• Still's Disease, Adult-Onset (blood)