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

Arthritis Rheum. 2001 Feb;44(2):275-85. doi: 10.1002/1529-0131(200102)44:2<275::AID-ANR44>3.0.CO;2-B.


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-gamma (IFNgamma) 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 IFNgamma 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 ofosteoarthritis (OA) patients, and serum IL-18 levels correlated with the levels of serum C-reactive protein. IFNgamma 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 IFNgamma production by RA synovial tissue cells, in contrast to IL-12, which was directly stimulatory. However, IL-12-induced IFNgamma 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 IFNgamma 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 IFNgamma-dominant T cell cytokine response in RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibody Formation / drug effects
  • Arthritis, Rheumatoid / metabolism*
  • Humans
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / physiology*
  • Interleukin-12 / pharmacology
  • Interleukin-18 / blood
  • Interleukin-18 / metabolism*
  • Interleukin-18 Receptor alpha Subunit
  • Joints / metabolism*
  • Osteoarthritis / metabolism
  • Receptors, Interleukin / antagonists & inhibitors
  • Receptors, Interleukin-18
  • Synovial Fluid / chemistry
  • Synovial Membrane / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism


  • IL18R1 protein, human
  • Interleukin-18
  • Interleukin-18 Receptor alpha Subunit
  • Receptors, Interleukin
  • Receptors, Interleukin-18
  • Interleukin-12
  • Interferon-gamma