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Local IL-18 gene transfer prevents severe joint destruction in murine collagen-induced arthritis by induction of IL-4 and osteoprotegerin


IL-18 is a member of the IL-1 family of proteins that exerts proinflammatory effects and is a pivotal cytokine for the development of T-cell-mediated immune responses. IL-18 can promote both the Th1 and Th2 pathways. Recent studies indicated IL-18 as an important stimulator of chronic inflammation in human diseases such as rheumatoid arthritis, Crohn's disease and several allergic disorders.


To investigate the aggravating effect of local IL-18 overexpression on both joint inflammation and joint destruction in murine collagen-induced arthritis.


Collagen-induced arthritis was induced in DBA-1 mice by intradermal injection of 100 μg bovine type II collagen in FCA. At day 21 the mice were boosted with 100 μg type II collagen. IL-18 gene transfer was performed on day 22 by intra-articular injection of 1 × 107 pfu AdmIL-18. As control we injected 1 × 107 pfu Ad5del70.3 Histopathology was examined at days 5 and 12 after AdIL-18 injection. Bone destruction was investigated using X-ray analysis. In addition, both systemic and local cytokine levels were determined in sera and patellae washouts, using a multiplex bead array (Luminex Technology). Osteoprotegerin levels were examined by ELISA.


Here we report that overexpression of IL-18 in knee joints of collagen type II primed DBA-1 mice resulted in aggravation of joint inflammation. Enhanced influx of proinflammatory cells, predominantly polymorphonuclear cells, was seen already at day 5 in both synovial tissue and the joint cavity. At day 12 extremely severe joint inflammation was seen in the AdIL-18 injected knee joint, whereas the Ad5del70.3-injected or saline-injected mice showed modest joint inflammation. Of high interest, although severe joint inflammation developed after IL-18 gene transfer, no signs of joint destruction were noted at day 12 after IL-18 overexpression. Histopathological and X-ray analysis revealed that both cartilage and bone destruction were completely prevented after intra-articular IL-18 exposure during collagen-induced arthritis. In addition, we found that local overexpression of IL-18 resulted in elevated levels for IL-4 in both serum (29 ± 14 versus 4 ± 3 pg/ml) and in synovial tissue washouts (1240 ± 220 versus 24 ± 7 pg/ml) when compared with Ad5del70.3. Remarkably high levels of osteoprotegerin were found in synovial tissue washouts at day 12 after IL-18 gene transfer compared with Ad5del70.3 vector (1570 ± 270 versus 210 ± 20 pg/ml). Moreover, local IL-10 levels were strongly enhanced whereas IL-1β levels were significantly reduced after IL-18 gene transfer.


The present study clearly demonstrated that local IL-18 overexpression accelerates joint inflammation, but prevents development of severe cartilage and bone destruction. High levels of both IL-4 and osteoprotegerin indicate establishment of a non-destructive type 2 inflammation. These data suggest that IL-18 may have a dual role in chronic destructive arthritis and that therapies based on local IL-18 blockade might be inadequate in rheumatoid arthritis.

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Joosten, L., Smeets, R., Koenders, M. et al. Local IL-18 gene transfer prevents severe joint destruction in murine collagen-induced arthritis by induction of IL-4 and osteoprotegerin. Arthritis Res Ther 7 (Suppl 1), P66 (2005).

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