Association of interleukin-18 expression with enhanced levels of both interleukin-1β and tumor necrosis factor α in knee synovial tissue of patients with rheumatoid arthritis
Corresponding Author
Leo A. B. Joosten
University Medical Center Nijmegen, Nijmegen, The Netherlands
Rheumatology Research Laboratory, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The NetherlandsSearch for more papers by this authorTimothy R. D. Radstake
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorErik Lubberts
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorLiduine A. M. van den Bersselaar
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorPiet L. C. M. van Riel
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorPeter L. E. M. van Lent
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorPilar Barrera
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorWim B. van den Berg
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorCorresponding Author
Leo A. B. Joosten
University Medical Center Nijmegen, Nijmegen, The Netherlands
Rheumatology Research Laboratory, University Medical Center Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The NetherlandsSearch for more papers by this authorTimothy R. D. Radstake
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorErik Lubberts
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorLiduine A. M. van den Bersselaar
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorPiet L. C. M. van Riel
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorPeter L. E. M. van Lent
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorPilar Barrera
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorWim B. van den Berg
University Medical Center Nijmegen, Nijmegen, The Netherlands
Search for more papers by this authorAbstract
Objective
To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation.
Methods
Biopsy specimens of knee synovial tissue either without synovitis (n = 6) or with moderate or severe synovitis (n = 11 and n = 12, respectively) were obtained from 29 patients with active RA. Paraffin-embedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor α (TNFα), IL-1β, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CD14, and CD68 were stained.
Results
IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1β (in the sublining r = 0.72, in the lining r = 0.71; both P < 0.0001) and TNFα (in the sublining r = 0.59, P < 0.0007, and in the lining r = 0.68, P < 0.0001). In addition, IL-18 expression in the sublining correlated with macrophage infiltration (r = 0.64, P < 0.0007) and microscopic inflammation scores (r = 0.78, P < 0.0001), and with the acute-phase reaction as measured by the erythrocyte sedimentation rate (r = 0.61, P < 0.0004). Interestingly, RA synovial tissue that coexpressed IL-18 and IL-12 demonstrated enhanced levels of the Th1-associated cytokine IL-17.
Conclusion
Our results show that expression of IL-18 is associated with that of IL-1β and TNFα and with local inflammation in the synovial tissue of patients with RA. In addition, synovial IL-18 expression correlates with the acute-phase response. These data indicate that IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1β and TNFα.
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