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
Corresponding Author
Marije I. Koenders
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Radboud University Nijmegen Medical Centre, Department of Rheumatology, Rheumatology Research and Advanced Therapeutics (272), Geert Grooteplein 28, PO Box 9101, 6500 HB Nijmegen, The NetherlandsSearch for more papers by this authorRenoud J. Marijnissen
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorIsabel Devesa
Radboud Universidad Miguel Hernández, Alicante, Spain
Search for more papers by this authorErik Lubberts
Erasmus Medical Centre, Rotterdam, The Netherlands
Search for more papers by this authorLeo A. B. Joosten
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorPeter L. E. M. van Lent
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorFons A. van de Loo
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorWim B. van den Berg
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorCorresponding Author
Marije I. Koenders
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Radboud University Nijmegen Medical Centre, Department of Rheumatology, Rheumatology Research and Advanced Therapeutics (272), Geert Grooteplein 28, PO Box 9101, 6500 HB Nijmegen, The NetherlandsSearch for more papers by this authorRenoud J. Marijnissen
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorIsabel Devesa
Radboud Universidad Miguel Hernández, Alicante, Spain
Search for more papers by this authorErik Lubberts
Erasmus Medical Centre, Rotterdam, The Netherlands
Search for more papers by this authorLeo A. B. Joosten
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorPeter L. E. M. van Lent
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorFons A. van de Loo
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorWim B. van den Berg
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Search for more papers by this authorAbstract
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.
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