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IL-18 expression in synovial biopsies of patients with active rheumatoid arthritis is associated with enhanced levels of both IL-1 and TNFα

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Objective

The present study was performed to examine the expression patterns of IL-18 in synovial biopsies of patients with active RA. In addition, we determined whether expression of this primary cytokine was related to expression of TNFα, IL-1β, IL-12, IL-17, and adhesion molecules or cell markers.

Methods

Synovial knee biopsies were taken from 29 patients with active RA and were immunohistochemically stained for TNFα, IL-1β, IL-12, IL-17, and IL-18. Furthermore, ICAM-1, VCAM-1, E-selectin, CD3, CD14, and CD68 were stained. Both paraffin and cryo-sections were used for the detection of cytokines, adhesion molecules or cell markers. Five biopsies per patient were analyzed.

Results

IL-18 staining was detectable in 80% of the RA patients both in lining and sublining. TNFα was present in 50% of the RA-patients, whereas IL-1β was seen in 90% of the patients. When staining for TNFα was positive, variable location of TNFα was seen in the synovial lining, sublining layer and endothelial cells. IL-1β staining was consistent in all three compartments. IL-12 was predominantly expressed in the sublining in 59% of the RA patients, whereas only 24% of the patients stained positive for IL-12 in the lining. Of interest, IL-17 staining was obvious in 70% of the RA patients, and only seen in the sublining layer. ICAM-1 and E-selectin staining was only seen in the endothelial cells, whereas VCAM-1 was noted in the synovial lining and endothelial cells. IL-18 expression in the synovial lining was positively correlated with both IL-1 (r = 0.71, P < 0.0001) and TNFα (r = 0.68, P < 0.0008). In addition, IL-18 expression correlated with both microscopic inflammation scores (r = 0.78, P < 0.0001) and macrophage marker CD68 (r = 0.64, P < 0.0007) expression. Furthermore, IL-18 was positively correlated with both acute phase markers ESR (r = 0.61, P < 0.0004) and CRP (r = 0.57, P > 0.001).

Conclusion

Our results showed that IL-18 expression is associated with elevated levels of TNFα, IL-1β in synovial biopsies of patients with active RA. In addition, synovial IL-18 expression correlates with both acute phase markers ESR and CRP. These data indicated that IL-18 is a primary proinflammatory cytokine in RA that drives local IL-1/TNFα production and may be involved in enhanced acute phase protein levels.

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Joosten, L., Barrera, P., Lubberts, E. et al. IL-18 expression in synovial biopsies of patients with active rheumatoid arthritis is associated with enhanced levels of both IL-1 and TNFα. Arthritis Res Ther 4, 16 (2002) doi:10.1186/ar455

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Keywords

  • Active Rheumatoid Arthritis
  • Synovial Lining
  • Synovial Biopsy
  • Sublining Layer
  • Microscopic Inflammation