Interferon-γ-inducing activity of interleukin-18 in the joint with rheumatoid arthritis

Masahiro Yamamura, Masanori Kawashima, Madoka Taniai, Hiroshi Yamauchi, Tadao Tanimoto, Masashi Kurimoto, Yoshitaka Morita, Yasukazu Ohmoto, Hirofumi Makino

Research output: Contribution to journalArticlepeer-review

118 Citations (Scopus)


Objective. To examine the levels of interleukin-18 (IL-18) bioactivity within the rheumatoid arthritis (RA) joint, and the differential effects of IL-12 and IL-18 on interferon-γ (IFNγ) production by T cell infiltrates. Methods. Expression of IL-18 protein and messenger RNA (mRNA) was determined by enzyme-linked immunosorbent assay and reverse transcriptase-polymerase chain reaction, respectively. The biologic activity of IL-18 was detected on the basis of IFNγ secretion from IL-18-responding human myelomonocytic KG-1 cells. To determine the extent of inhibitory activity on binding of IL-18 to its receptor, a [125I]-IL-18 binding inhibition assay was performed, using a Chinese hamster ovary cell line transfected with a murine IL-18 receptor. Results. The amount of IL-18 protein detected in both the serum and synovial fluid of RA patients was markedly larger than that detected in the serum and synovial fluid of osteoarthritis (OA) patients, and serum IL-18 levels correlated with the levels of serum C-reactive protein. IFNγ production by KG-1 cells was more strongly stimulated in synovial fluid samples from RA patients than in samples from OA patients, and this activity was largely diminished in the presence of anti-IL-18 antibody. In contrast, the activity of IL-18 binding inhibition in the serum and synovial fluid of RA patients was not significantly elevated compared with that in OA patients. RA synovial tissues showed increased expression of IL-18 mRNA and increased IL-18 protein synthesis compared with that in OA tissues. Purified CD14+ macrophages, but not activated fibroblast cell lines, from RA synovium were able to release mature IL-18, although both cell types expressed its transcripts. IL-18 alone showed a negligible effect on IFNγ production by RA synovial tissue cells, in contrast to IL-12, which was directly stimulatory. However, IL-12-induced IFNγ production was synergistically enhanced by IL-18, and yet was >50% reduced by neutralization of endogenous IL-18 with anti-IL-18 antibody. Conclusion. These results indicate that IL-18, produced predominantly by tissue macrophages, primarily potentiates IL-12-induced IFNγ production by T cell infiltrates in RA synovium. Detection of significant IL-18 bioactivity in the joints, despite the presence of IL-18 binding inhibitors, supports an integral role of this cytokine in perpetuating the IFNγ-dominant T cell cytokine response in RA.

Original languageEnglish
Pages (from-to)275-285
Number of pages11
JournalArthritis and Rheumatism
Issue number2
Publication statusPublished - 2001

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Pharmacology (medical)


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