白细胞介素-1在白细胞介素-1受体拮抗剂缺陷小鼠的自发性关节炎中驱动致病性辅助性T细胞17（Th17）细胞。

Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice.

作者信息

Koenders Marije I, Devesa Isabel, Marijnissen Renoud J, Abdollahi-Roodsaz Shahla, Boots Annemieke M H, Walgreen Birgitte, di Padova Franco E, Nicklin Martin J H, Joosten Leo A B, van den Berg Wim B

机构信息

Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

出版信息

Arthritis Rheum. 2008 Nov;58(11):3461-70. doi: 10.1002/art.23957.

DOI:10.1002/art.23957

PMID:18975337

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.

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.

摘要

目的

白细胞介素-1受体拮抗剂缺陷（IL-1Ra-/-）小鼠由于白细胞介素-1信号未受抑制而过度表达，会自发发展出炎症性和破坏性关节炎。在本研究中，在这个由白细胞介素-1驱动的小鼠关节炎模型中，研究了辅助性T细胞17（Th17）细胞的作用以及中和白细胞介素-17、白细胞介素-1和肿瘤坏死因子α（TNFα）的效果。

方法

从IL-1Ra-/-和野生型（WT）小鼠中分离出的T细胞用白细胞介素-17和干扰素-γ进行染色，结果通过荧光激活细胞分选分析进行评估。为了研究白细胞介素-1和白细胞介素-17在该模型中关节炎进一步发展中的作用，在关节炎发作后用中和抗体对小鼠进行治疗。

结果

与WT小鼠相比，IL-1Ra-/-小鼠的Th1细胞水平相似，但Th17细胞水平明显升高；即使在关节炎发作之前，在年轻的非关节炎IL-1Ra-/-小鼠中，Th17细胞数量的增加也很明显。关节炎发作后，Th17细胞的百分比进一步增加，并且与白细胞介素-17的血清水平和局部信使核糖核酸水平相似，IL-17+Th17细胞的百分比与关节炎的严重程度明显相关。抗白细胞介素-17治疗可防止炎症和骨侵蚀的进一步增加，而在关节炎发作后阻断TNFα则没有效果。相比之下，中和白细胞介素-1可导致关节炎完全得到抑制。有趣的是，这种抗白细胞介素-1治疗还显著降低了这些关节炎小鼠引流淋巴结中IL-17+Th17细胞的百分比。