Interferon-γ regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17
Interferon-γ regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17
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DOI：
10.1002/art.22453
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发表时间：
2007-04-01
影响因子：
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通讯作者：
Elkon, Keith B.
中科院分区：
文献类型：
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作者：
Chu, Cong-Qiu;Swart, David;Elkon, Keith B.
目的。在缺乏干扰素 -γ（IFN -γ）的情况下实验性关节炎表达增强，这表明IFN -γ可抑制关节炎。白细胞介素 -17（IL -17）是关节炎中一种关键的T细胞细胞因子，体外研究表明IFN -γ可抑制IL -17的产生。我们进行这项研究以验证以下假说：C57BL/6（B6）小鼠对胶原诱导性关节炎（CIA）的抵抗是由IFN -γ介导的对IL -17的抑制所调控的。
方法。野生型（WT）B6小鼠、IFN -γ基因敲除（KO）B6小鼠和DBA/1小鼠用弗氏完全佐剂（CFA）中的II型胶原（CII）进行免疫。通过细胞内染色或用CII再刺激以及酶联免疫吸附测定，对免疫小鼠的淋巴细胞进行体外细胞因子产生分析。用抗IL -17单克隆抗体（mAb）实现体内对IL -17的阻断。
结果。用CII/CFA免疫的小鼠的T细胞经CII再刺激后，与野生型B6小鼠相比，IFN -γ基因敲除B6小鼠的IL -17产生增加了约5倍。中和IFN -γ会使野生型B6小鼠的IL -17产生增加，而中和IL -4具有协同作用。有趣的是，与野生型B6小鼠相比，典型的CIA易感品系DBA/1也表现出高IL -17和低IFN -γ细胞因子特征。给予抗IL -17单克隆抗体可减轻DBA/1小鼠的关节炎，并几乎完全阻止IFN -γ基因敲除B6小鼠的关节炎发作。
结论。这些结果表明，IFN -γ缺陷型B6小鼠对CIA的敏感性与高IL -17产生相关，并且这种细胞因子是该品系关节炎发作所必需的。
Objective. The enhanced expression of experimental arthritis in the absence of interferon-gamma (IFN gamma) suggests that IFN gamma suppresses arthritis. Interleukin-17 (IL-17) is a pivotal T cell cytokine in arthritis, and in vitro studies have indicated that IFN gamma suppresses IL-17 production. We undertook this study to test the hypothesis that resistance to collagen-induced arthritis (CIA) in C57BL/6 (136) mice is regulated by IFN gamma-mediated suppression of IL-17.Methods. Wild-type (WT) B6 mice, IFN gamma-knockout (KO) B6 mice, and DBA/1 mice were immunized with type II collagen (CII) in Freund's complete adjuvant (CFA). Lymphocytes from immunized mice were analyzed for cytokine production ex vivo by intracellular staining or restimulation with CII and enzyme-linked immunosorbent assays. In vivo blockade of IL-17 was achieved with an anti-IL-17 monoclonal antibody (mAb).Results. CII restimulation of T cells from CII/CFA-immunized mice resulted in an similar to 5-fold increase in IL-17 production in IFN gamma-KO B6 mice compared with WT B6 mice. Neutralization of IFN gamma increased IL-17 production in WT B6 mice, and neutralization of IL-4 had a synergistic effect. Interestingly, the prototypical CIA-susceptible strain DBA/1 also demonstrated a high IL-17 and a low IFN gamma cytokine profile compared with WT B6 mice. Administration of the anti-IL-17 mAb attenuated arthritis in DBA/1 mice and almost completely prevented expression of arthritis in IFN gamma-KO B6 mice.Conclusion. These results indicate that sensitivity of IFN gamma-deficient B6 mice to CIA is associated with high IL-17 production and that this cytokine is required for expression of arthritis in this strain.