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. CONCLUSION: 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.
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 murinearthritis 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. CONCLUSION: 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: Sarah R Pickens; Michael V Volin; Arthur M Mandelin; Jay K Kolls; Richard M Pope; Shiva Shahrara Journal: J Immunol Date: 2010-02-19 Impact factor: 5.422
Authors: Ivona Aksentijevich; Seth L Masters; Polly J Ferguson; Paul Dancey; Joost Frenkel; Annet van Royen-Kerkhoff; Ron Laxer; Ulf Tedgård; Edward W Cowen; Tuyet-Hang Pham; Matthew Booty; Jacob D Estes; Netanya G Sandler; Nicole Plass; Deborah L Stone; Maria L Turner; Suvimol Hill; John A Butman; Rayfel Schneider; Paul Babyn; Hatem I El-Shanti; Elena Pope; Karyl Barron; Xinyu Bing; Arian Laurence; Chyi-Chia R Lee; Dawn Chapelle; Gillian I Clarke; Kamal Ohson; Marc Nicholson; Massimo Gadina; Barbara Yang; Benjamin D Korman; Peter K Gregersen; P Martin van Hagen; A Elisabeth Hak; Marjan Huizing; Proton Rahman; Daniel C Douek; Elaine F Remmers; Daniel L Kastner; Raphaela Goldbach-Mansky Journal: N Engl J Med Date: 2009-06-04 Impact factor: 91.245
Authors: Christophe Cataisson; Rosalba Salcedo; Aleksandra M Michalowski; Mary Klosterman; Shruti Naik; Luowei Li; Michelle J Pan; Amalia Sweet; Jin-Qiu Chen; Laurie G Kostecka; Megan Karwan; Loretta Smith; Ren-Ming Dai; C Andrew Stewart; Lyudmila Lyakh; Wang-Ting Hsieh; Asra Khan; Howard Yang; Maxwell Lee; Giorgio Trinchieri; Stuart H Yuspa Journal: Mol Cancer Res Date: 2019-06-04 Impact factor: 5.852