Protective role of IFN-γ in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production
Protective role of IFN-γ in collagen-induced arthritis conferred by inhibition of mycobacteria-induced granulocyte chemotactic protein-2 production
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DOI：
10.1189/jlb.0806486
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发表时间：
2007-04-01
影响因子：
5.5
通讯作者：
Matthys, Patrick
中科院分区：
文献类型：
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作者：
Kelchtermans, Hilde;Struyf, Sofie;Matthys, Patrick
IFN-γ系统受损的小鼠对实验性自身免疫性疾病非常敏感，如胶原诱导的关节炎（CIA），这依赖于CFA的使用。这些IFN-γ敲除（KO）小鼠的炎性病变的特征在于中性粒细胞比例过高。在这里，我们表明，与野生型小鼠相比，IFN-γ R KO中CIA的严重程度增加伴随着CXC趋化因子粒细胞趋化蛋白-2（GCP-2）水平的增加，GCP-2是小鼠中一种主要的嗜中性粒细胞吸引趋化因子。我们证明了CFA中存在的热灭活分枝杆菌在小鼠胚胎成纤维细胞培养物中引起GCP-2的产生，并且这种产生被IFN-γ抑制。IFN-γ对GCP-2产生的抑制是STAT-1依赖性的。用中和性抗GCP-2抗体处理的IFN-γ受体KO小鼠受到保护免于CIA，表明GCP-2在CIA发病机制中的体内重要性。我们的数据支持这样的观点，即内源性IFN-γ减轻CIA表现的机制之一包括抑制GCP-2的产生，从而限制中性粒细胞的动员和浸润，这是关节炎症的重要因素。这些结果也可能适用于依赖于使用CFA的其他自身免疫实验模型。
Mice with a disrupted IFN-gamma system are remarkably susceptible to experimental autoimmune diseases, such as collagen-induced arthritis (CIA), which rely on the use of CFA. The inflammatory lesions of these IFN-gamma knockout (KO) mice are characterized by an excessive proportion of neutrophils. Here, we show that the increased severity of CIA in IFN-gamma R KO as compared with wild-type mice is accompanied by increased levels of the CXC chemokine granulocyte chemotactic protein-2 (GCP-2), a major neutrophil-attracting chemokine in mice. We demonstrated that the heat-killed mycobacteria present in CFA elicited production of GCP-2 in mouse embryo fibroblast cultures and that this production was inhibited by IFN-gamma. Inhibition of GCP-2 production by IFN-gamma was STAT-1-dependent. IFN-gamma receptor KO mice treated with neutralizing anti-GCP-2 antibodies were protected from CIA, indicating the in vivo importance of GCP-2 in the pathogenesis of CIA. Our data support the notion that one of the mechanisms whereby endogenous IFN-gamma mitigates the manifestations of CIA consists of inhibiting production of GCP-2, thereby limiting mobilization and infiltration of nentrophils, which are important actors in joint inflammation. These results may also be applicable to other experimental models of autoimmunity that rely on the use of CFA.