IL-4 confers resistance to IL-27-mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling.
IL-4 confers resistance to IL-27-mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling.
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DOI：
10.1016/j.jaci.2013.06.035
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发表时间：
2013-10
期刊：
影响因子：
--
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Chen Z;Wang S;Erekosima N;Li Y;Hong J;Qi X;Merkel P;Nagabhushanam V;Choo E;Katial R;Alam R;Trikha A;Chu HW;Zhuang Y;Jin M;Bai C;Huang H
Th2细胞在过敏性哮喘的发病机制中起关键作用。已建立的Th2细胞已被证明抵抗重新编程为Th1细胞。Th2细胞固有的稳定性是治疗变态反应性疾病的重要障碍。我们试图了解哮喘患者的CD4+T细胞抵抗IL-27介导的抑制的机制。我们分离和培养了正常人和过敏性哮喘患者的CD4+T细胞，以检测IL-27是否能抑制培养的CD4+T细胞产生IL-4。用小鼠和人的CD4+T细胞培养系统确定了导致对IL-27产生抵抗力的培养条件。用Western印迹和流式细胞术分析STAT1的磷酸化。定量聚合酶链式反应检测细胞因子信号转导抑制因子(SOCS)基因的表达。采用小干扰RNA方法下调SOCS3mRNA的表达。我们证明了哮喘患者的CD4+T细胞抵抗了IL-27介导的IL-4产生的抑制。我们观察到，反复暴露在Th2诱导的条件下，使健康的人类CD4+T细胞抵抗IL-27介导的抑制。利用小鼠体外培养系统，我们进一步证明了重复或更高剂量的IL-4刺激，而不是IL-2刺激，上调了SOCS3mRNA的表达，并削弱了IL-27诱导的STAT1的磷酸化。SOCS3基因表达下调可恢复IL-27诱导的STAT1磷酸化和IL-27对IL-4产生的抑制作用。我们的发现表明，分化的Th2细胞可以通过下调STAT1的磷酸化来抵抗IL-27诱导的向Th1细胞的重编程，这可能解释了为什么哮喘患者的CD4+T细胞对IL-27介导的抑制具有抵抗作用。
Th2 cells play a critical role in the pathogenesis of allergic asthma. Established Th2 cells have been shown to resist reprogramming into Th1 cells. The inherent stability of Th2 cells poses a significant barrier to treating allergic diseases. We sought to understand the mechanisms by which CD4+ T cells from asthmatic patients resist the IL-27-mediated inhibition. We isolated and cultured CD4+ T cells from both healthy individuals and allergic asthmatic patients in order to test whether IL-27 can inhibit IL-4 production by the cultured CD4+ T cells using ELISA. Culturing conditions that resulted in resistance to IL-27 were determined using both murine and human CD4+ T cell culture systems. STAT1 phosphorylation was analyzed by Western blot and flow cytometry. Suppressor of cytokine signaling (Socs) mRNA expression was measured by quantitative PCR. The small interfering RNA method was used to knockdown the expression of Socs3 mRNA. We demonstrated that CD4+ T cells from asthmatic patients resisted the suppression of IL-4 production mediated by IL-27. We observed that repeated exposure to Th2-inducing conditions rendered healthy human CD4+ T cells resistant to IL-27-mediated inhibition. Using an in vitro murine culture system, we further demonstrated that repeated or higher doses of IL-4 stimulation, but not IL-2 stimulation, upregulated Socs3 mRNA expression and impaired IL-27-induced STAT1 phosphorylation. The Knockdown of Socs3 mRNA expression restored IL-27-induced STAT1 phosphorylation and IL-27-mediated inhibition of IL-4-production. Our findings demonstrate that differentiated Th2 cells can resist IL-27-induced reprogramming toward Th1 cells by downregulating STAT1 phosphorylation and likely explain why the CD4+ T cells of asthmatic patients are resistant to IL-27-mediated inhibition.
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影响因子：
30.8
作者：
Dupuis, S;Jouanguy, E;Casanova, JL
通讯作者：
Casanova, JL
影响因子：
4.4
作者：
Huang, Z;Xin, JP;Huang, H
通讯作者：
Huang, H
影响因子：
32.4
作者：
Elo, Laura L.;Jarvenpaa, Henna;Lahesmaa, Riitta
通讯作者：
Lahesmaa, Riitta
影响因子：
3.2
作者：
Fukushima, A;Yamaguchi, T;Ueno, H
通讯作者：
Ueno, H
DOI：
10.1073/pnas.2536517100
发表时间：
2003-12-09
影响因子：
11.1
作者：
Lucas, S;Ghilardi, N;de Sauvage, FJ
通讯作者：
de Sauvage, FJ