Tumor necrosis factor–interleukin-17 interplay induces S100A8, interleukin-1β, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: Rationale for combination treatment during arthritis
Article first published online: 1 AUG 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 8, pages 2329–2339, August 2011
How to Cite
Koenders, M. I., Marijnissen, R. J., Devesa, I., Lubberts, E., Joosten, L. A. B., Roth, J., van Lent, P. L. E. M., van de Loo, F. A. and van den Berg, W. B. (2011), Tumor necrosis factor–interleukin-17 interplay induces S100A8, interleukin-1β, and matrix metalloproteinases, and drives irreversible cartilage destruction in murine arthritis: Rationale for combination treatment during arthritis. Arthritis & Rheumatism, 63: 2329–2339. doi: 10.1002/art.30418
- Issue published online: 1 AUG 2011
- Article first published online: 1 AUG 2011
- Accepted manuscript online: 22 APR 2011 01:32PM EST
- Manuscript Accepted: 14 APR 2011
- Manuscript Received: 1 SEP 2010
- Dutch Arthritis Association. Grant Number: NR 00-1-302
- Stichting De Drie Lichten, Hilversum, The Netherlands
To examine whether synovial interleukin-17 (IL-17) expression promotes tumor necrosis factor (TNF)–induced joint pathologic processes in vivo, and to analyze the surplus ameliorative value of neutralizing IL-17 in addition to TNF during collagen-induced arthritis (CIA).
Adenoviral vectors were used to induce overexpression of IL-17 and/or TNF in murine knee joints. In addition, mice with CIA were treated, at different stages of arthritis, with soluble IL-17 receptor (sIL-17R), TNF binding protein (TNFBP), or the combination.
Overexpression of IL-17 and TNF resulted in joint inflammation and bone erosion in murine knees. Interestingly, IL-17 strikingly enhanced both the joint-inflammatory and joint-destructive capacity of TNF. Further analysis revealed a strongly enhanced up-regulation of S100A8, IL-1β, and matrix metalloproteinase (MMP) messenger RNA, only when both TNF and IL-17 were present. Moreover, the increase in irreversible cartilage destruction was not merely the result of enhanced inflammation, but also was associated with a direct synergistic effect of these cytokines in the joint. S100A9 deficiency in mice protected against IL-17/TNF–induced expression of cartilage NITEGE neoepitopes. During established arthritis, the combination of sIL-17R and TNFBP was more effective than the anticytokine treatments alone, and significantly inhibited further joint inflammation and cartilage destruction.
Local synovial IL-17 expression enhances the role of TNF in joint destruction. Synergy between TNF and IL-17 in vivo results in striking exaggeration of cartilage erosion, in parallel with a synergistic up-regulation of S100A8, IL-1β, and erosive MMPs. Moreover, neutralizing IL-17 in addition to TNF further improves protection against joint damage and is still effective during late-stage CIA. Therefore, compared with anti-TNF alone, combination blocking of TNF and IL-17 may have additional therapeutic value for the treatment of destructive arthritis.