title: Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice.
abstract: OBJECTIVE
  Interleukin-1 receptor antagonist-deficient (IL-1Ra-/-) mice spontaneously develop an inflammatory and destructive arthritis due to unopposed excess IL-1 signaling. In this study, the role of Th17 cells and the effect of neutralization of IL-17, IL-1, and tumor necrosis factor alpha (TNFalpha) were investigated in this IL-1-driven murine arthritis model.
  
  
  METHODS
  T cells isolated from IL-1Ra-/- and wild-type (WT) mice were stained for IL-17 and interferon-gamma, with results assessed by fluorescence-activated cell sorting analysis. To investigate the contribution of IL-1 and IL-17 in further progression of arthritis in this model, mice were treated with neutralizing antibodies after the onset of arthritis.
  
  
  RESULTS
  Compared with WT mice, IL-1Ra-/- mice had similar levels of Th1 cells but clearly enhanced levels of Th17 cells; this increase in the number of Th17 cells was evident even before the onset of arthritis, in young, nonarthritic IL-1Ra-/- mice. The percentage of Th17 cells increased even more after the onset of arthritis and, similar to the serum levels and local messenger RNA levels of IL-17, the percentage of IL-17+ Th17 cells clearly correlated with the severity of arthritis. Anti-IL-17 treatment prevented any further increase in inflammation and bone erosion, whereas blocking of TNFalpha after the onset of arthritis had no effect. In contrast, neutralization of IL-1 resulted in a complete suppression of arthritis. Interestingly, this anti-IL-1 treatment also significantly reduced the percentage of IL-17+ Th17 cells in the draining lymph nodes of these arthritic mice.
  
  
  CONCLUSIONS
  Increased levels of Th17 cells can be detected in IL-1Ra-/- mice even preceding the onset of arthritis. In addition, the results of cytokine-blocking studies demonstrated that IL-17 contributes to the inflammation and bone erosion in this model, which suggests that IL-1 is the driving force behind the IL-17-producing Th17 cells.
authors.affiliation: Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. m.koenders@reuma.umcn.nl
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Isabel
authors.initials: I
authors.lastname: Devesa
authors.forename: Renoud J
authors.initials: RJ
authors.lastname: Marijnissen
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.forename: Annemieke M H
authors.initials: AM
authors.lastname: Boots
authors.forename: Birgitte
authors.initials: B
authors.lastname: Walgreen
authors.forename: Franco E
authors.initials: FE
authors.lastname: di Padova
authors.forename: Martin J H
authors.initials: MJ
authors.lastname: Nicklin
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000503:physiopathology*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency*; D007375:Interleukin-1 / Q000502:physiology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016176:T-Lymphocyte Subsets / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha