Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A.
Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A.
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DOI：
10.1136/annrheumdis-2013-203771
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发表时间：
2013-10
影响因子：
27.4
通讯作者：
Jones SA
中科院分区：
文献类型：
--
作者：
Jones GW;Greenhill CJ;Williams JO;Nowell MA;Williams AS;Jenkins BJ;Jones SA
产生白细胞介素（IL）-17 A的CD 4 T细胞（TH-17细胞）与类风湿性关节炎（RA）有关。IL-6/STAT 3信号传导驱动TH-17细胞分化，并且gp 130 F/F小鼠中过度活跃的gp 130/STAT 3信号传导促进恶化的病理。相反，STAT 1激活细胞因子（例如，IL-27、IFN-γ）抑制TH-17定型。在这里，我们评估了STAT 1消融对实验性关节炎期间TH-17细胞的影响，并将其与IL-17 A相关的病理学联系起来。在野生型（WT）、gp 130介导的STAT信号转导过度活跃的gp 130 F/F小鼠以及复合突变体gp 130 F/F：Stat 1 −/−和gp 130 F/F：Il 17 a −/−小鼠中建立抗原诱导性关节炎（AIA）。比较了关节病理学和相关的外周TH-17反应。增强的gp 130/STAT 3信号转导增强了体外TH-17定型并加剧了关节病理学。在AIA过程中，gp 130 F/F小鼠（gp 130 F/F：Stat 1-/-）中STAT 1的消融促进了体外和体内TH-17细胞的过度膨胀。尽管外周TH-17细胞应答增强，但疾病严重程度和关节浸润T细胞的数量与WT小鼠相当。因此，炎症滑膜中gp 130介导的STAT 1活性控制着T细胞的运输和滞留。为了确定IL-17 A的贡献，我们产生了gp 130 F/F：IL-17 a −/−小鼠。在这里，IL-17 A的缺失对关节炎的严重程度没有影响。AIA中gp 130/STAT驱动的疾病加重与关节浸润性T细胞增加相关，但滑膜病理学不依赖于IL-17 A。
Interleukin (IL)-17A producing CD4 T-cells (TH-17 cells) are implicated in rheumatoid arthritis (RA). IL-6/STAT3 signalling drives TH-17 cell differentiation, and hyperactive gp130/STAT3 signalling in the gp130F/F mouse promotes exacerbated pathology. Conversely, STAT1-activating cytokines (eg, IL-27, IFN-γ) inhibit TH-17 commitment. Here, we evaluate the impact of STAT1 ablation on TH-17 cells during experimental arthritis and relate this to IL-17A-associated pathology. Antigen-induced arthritis (AIA) was established in wild type (WT), gp130F/F mice displaying hyperactive gp130-mediated STAT signalling and the compound mutants gp130F/F:Stat1−/− and gp130F/F:Il17a−/− mice. Joint pathology and associated peripheral TH-17 responses were compared. Augmented gp130/STAT3 signalling enhanced TH-17 commitment in vitro and exacerbated joint pathology. Ablation of STAT1 in gp130F/F mice (gp130F/F:Stat1−/−) promoted the hyperexpansion of TH-17 cells in vitro and in vivo during AIA. Despite this heightened peripheral TH-17 cell response, disease severity and the number of joint-infiltrating T-cells were comparable with that of WT mice. Thus, gp130-mediated STAT1 activity within the inflamed synovium controls T-cell trafficking and retention. To determine the contribution of IL-17A, we generated gp130F/F:IL-17a−/− mice. Here, loss of IL-17A had no impact on arthritis severity. Exacerbated gp130/STAT-driven disease in AIA is associated with an increase in joint infiltrating T-cells but synovial pathology is IL-17A independent.
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DOI：
10.1084/jem.20061775
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sato K;Suematsu A;Okamoto K;Yamaguchi A;Morishita Y;Kadono Y;Tanaka S;Kodama T;Akira S;Iwakura Y;Cua DJ;Takayanagi H
通讯作者：
Takayanagi H
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
32.4
作者：
Veldhoen, M;Hocking, RJ;Stockinger, B
通讯作者：
Stockinger, B
影响因子：
--
作者：
van Hamburg, J. P.;Asmawidjaja, P. S.;Lubberts, E.
通讯作者：
Lubberts, E.
影响因子：
7.3
作者：
Kennedy, Catherine L.;Najdovska, Men;Jenkins, Brendan J.
通讯作者：
Jenkins, Brendan J.