Volume 5 Supplement 1

23rd European Workshop for Rheumatology Research

Open Access

IL-18 directly promotes joint inflammation and induces cartilage destruction through IL-1

  • L Joosten1,
  • E Lubberts1,
  • MJM Wagenmans1,
  • MMA Helsen1,
  • FAJ van de Loo1 and
  • WB van den Berg1
Arthritis Res Ther20035(Suppl 1):43

DOI: 10.1186/ar673

Received: 14 January 2003

Published: 24 February 2003

Background

Interleukin-18 is a member of the IL-1 family of proteins that exerts proinflammatory effects and induces cartilage destruction in vitro.

Objective

The goal of the present study was to investigate whether IL-18 mediates joint destruction in vivo, directly or via induction of other cytokines.

Results

To this end, we performed both in vitro and in vivo kinetic studies. 35S-labeled explants of C57Bl/6 mice were cultured for 24 to 72 hours in either IGF-1, IGF-1/IL-18 or IGF-1/IL-1β in combination with or without IL-1 receptor antagonist (IL-1Ra) or an ICE inhibitor. Wild-type, TNFα-deficient and IL-1α,β-deficient mice were used for in vivo IL-18 exposure studies. Mice were injected intra-articularly with 107 pfu mIL-18 adenovirus at day 0, and histopathology was examined at days 4, 7 and 14. In vitro IL-18 exposure for 24 or 48 hours did not induce cartilage degradation, determined as release of prelabeled proteoglycans. Cartilage degradation by IL-18 was only found after a 72-hour culture period. Blocking of IL-1 with IL-1Ra or ICE-inhibitor resulted in almost complete protection against IL-18 mediated cartilage degradation in vitro. Application of 107 pfu AdmIL-18 resulted in prolonged elevated levels of IL-18, for up to 14 days. Histology at days 4, 7, and 14 revealed that local overexpression of IL-18 resulted in increasing joint inflammation and cartilage destruction in the wild-type mice. Of high interest, IL-18 gene transfer in IL-1α,β-/- mice did not show cartilage damage at the various time points, although joint inflammation was similar to that in the wild-type animals. Overexpression of IL-18 in TNFα-deficient mice showed that TNFα was partly involved in IL-18-induced joint inflammation.

Conclusion

Here we showed that IL-18 induces joint inflammation independently of IL-1. In addition, we showed that IL-1 generation, due to IL-18 exposure, was essential for marked cartilage degradation both in vitro and in vivo. These findings imply that IL-18 contributes, through separate pathways, to joint inflammation and cartilage destruction.

Authors’ Affiliations

(1)
Rheumatology Research Laboratory, University Medical Center Nijmegen

Copyright

© The Author(s) 2003

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