Point mutation of tyrosine 759 of the IL-6 family cytokine receptor, gp130, augments collagen-induced arthritis in DBA/1J mice
Point mutation of tyrosine 759 of the IL-6 family cytokine receptor, gp130, augments collagen-induced arthritis in DBA/1J mice
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DOI：
10.1186/1471-2474-10-23
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发表时间：
2009-02-19
影响因子：
2.3
通讯作者：
Aono, Hiroyuki
中科院分区：
文献类型：
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作者：
Tsuji, Fumio;Yoshimi, Miwa;Aono, Hiroyuki
背景资料：在gp 130（IL-6细胞因子家族成员共有的信号转导受体亚基）中具有Y 759 F点突变的敲入小鼠（gp 130 F759）显示持续的STAT 3活化、增强的急性期或免疫应答和自身免疫性关节炎。方法：将gp 130 F759与C57 BL/6和DBA/1 J进行回交，比较两种不同遗传背景的gp 130 F759与C57 BL/6和DBA/1 J的病理变化，包括关节炎的发生。结果：C57 BL/6背景gp 130 F759小鼠自发性发生多发性关节炎和肾小球肾炎，而D/J.gp130F759小鼠无此现象。另一方面，眼睛的角膜炎仅在D/J.gp130F759中发生，表明遗传背景对gp 130 F759小鼠中疾病发展的影响。DBA/1 J背景对自发性关节炎的抗性促使我们在D/J.gp130F759中检查CIA。D/J.gp130F759中的CIA比对照小鼠更严重，具有更大的骨破坏。胶原免疫后，脾肿大和类风湿因子和抗DNA抗体的血清水平增加D/J.gp130F759。血清细胞因子的生物学分析显示免疫前IL-12 p40和PDGF-BB增加，加强剂量后8天IFN-γ、IL-17、TNF-α、IL-9和MIP-1 β水平增加。D/J.gp130F759中的IL-6和PDGF-BB显示出与其他细胞因子不同的动力学;在关节炎发展后观察到更高的水平。MTX可部分减轻D/J.gp130F759关节炎的发生，抑制骨破坏，降低抗II型胶原抗体水平，提示MTX主要影响CIA的抗原特异性免疫反应。结论：IL-6家族细胞因子受体亚基gp 130的Tyr-759点突变引起自身免疫性疾病，这也受遗传背景的影响。D/J.gp130F759中的CIA对于在相对短的时间内评价药物是有用的，因为STAT 3的持续激活可以增强疾病症状。
Background: Knock-in mice (gp130F759) with a Y759F point mutation in gp130, a signal transducing receptor subunit shared by members of the IL-6 cytokine family, show sustained activation of STAT3, enhanced acute-phase or immune responses, and autoimmune arthritis. We conducted a detailed analysis of collagen-induced arthritis (CIA) in gp130F759 with a DBA/1J background (D/J.gp130F759).Methods: We backcrossed gp130F759 to C57BL/6 and DBA/1J, and compared the pathologic changes, including occurrence of arthritis, in the two distinct genetic backgrounds. We analyzed CIA in D/J.gp130F759 and investigated the effects of methotrexate (MTX) on CIA.Results: C57BL/6 background gp130F759 mice, but not D/J.gp130F759, spontaneously developed polyarthritis and glomerulonephritis. On the other hand, keratitis of the eyes only developed in D/J.gp130F759, indicating the influence of genetic background on disease development in gp130F759 mice. Resistance of the DBA/1J background against spontaneous arthritis urged us to examine CIA in D/J.gp130F759. CIA in D/J.gp130F759 was more severe, with greater bone destruction, than the control mice. After collagen immunization, splenomegaly and serum levels of rheumatoid factor and anti-DNA antibody were augmented in D/J.gp130F759. Bio-Plex analysis of serum cytokines revealed increased IL-12p40 and PDGF-BB before immunization, and increased levels of IFN-gamma, IL-17, TNF-alpha, IL-9, and MIP-1 beta 8 days after the booster dose. IL-6 and PDGF-BB in D/J.gp130F759 showed distinct kinetics from the other cytokines; higher levels were observed after arthritis development. MTX partially attenuated the development of arthritis and inhibited bone destruction in D/J.gp130F759, with reduction of anti-type II collagen antibody levels, suggesting that MTX mainly affects antigen-specific immune responses in CIA.Conclusion: The Tyr-759 point mutation of the IL-6 family cytokine receptor subunit, gp130, caused autoimmune disease, and this was also influenced by the genetic background. CIA in D/J.gp130F759 is useful for evaluating drugs in a relatively short period because sustained activation of STAT3 may enhance the disease symptoms.