title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Rheumatology, Nijmegen, The Netherlands. m.koenders@reuma.umcn.nl
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Renoud J
authors.initials: RJ
authors.lastname: Marijnissen
authors.forename: Isabel
authors.initials: I
authors.lastname: Devesa
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Peter L E M
authors.initials: PL
authors.lastname: van Lent
authors.forename: Fons A
authors.initials: FA
authors.lastname: van de Loo
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism* / Q000473:pathology; D040501:Calgranulin A / Q000378:metabolism*; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D040501:Calgranulin A; D020381:Interleukin-17; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases