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Interleukin‐1 drives pathogenic Th17 cells during spontaneous arthritis in interleukin‐1 receptor antagonist–deficient mice
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 α (TNFα) wer...
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Published in: | Arthritis and rheumatism 2008-11, Vol.58 (11), p.3461-3470 |
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Main Authors: | , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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 α (TNFα) 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‐γ, 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 TNFα 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. |
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ISSN: | 0004-3591 1529-0131 |
DOI: | 10.1002/art.23957 |