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.
In: Arthritis & Rheumatism, Jg. 63 (2011-08-01), Heft 8, S. 2329-2339
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Zugriff:
Objective 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). Methods 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. Results 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. Conclusion 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. [ABSTRACT FROM AUTHOR]
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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.
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Autor/in / Beteiligte Person: | Koenders, Marije I. ; Marijnissen, Renoud J. ; Devesa, Isabel ; Lubberts, Erik ; Joosten, Leo A. B. ; Roth, Johannes ; van Lent, Peter L. E. M. ; van de Loo, Fons A. ; van den Berg, Wim B. |
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Zeitschrift: | Arthritis & Rheumatism, Jg. 63 (2011-08-01), Heft 8, S. 2329-2339 |
Veröffentlichung: | 2011 |
Medientyp: | academicJournal |
ISSN: | 0004-3591 (print) |
DOI: | 10.1002/art.30418 |
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