CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH cytokine production
CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH cytokine production
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DOI：
10.1016/j.jaci.2005.09.035
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发表时间：
2005-12-01
影响因子：
14.2
通讯作者：
Annunziato, F
中科院分区：
文献类型：
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作者：
Romagnani, P;Maggi, L;Annunziato, F
背景：CXCR3受体存在两种变体，一种（CXCR3- a）与CXCL9、CXCL10和CXCL11反应，另一种（CXCR3- b）也与CXCL4反应。这两种变体在人类T细胞中同时表达。目的：探讨CXCL10和CXCL4在体外对T(H)1或T(H)2细胞因子产生的影响。方法：采用定量RT-PCR、流式细胞术和ELISA方法，对CXCL10或CXCL4缺失或存在情况下获得的抗原特异性人CD4(+) t细胞系的细胞因子谱进行评估。结果：CXCL10上调ifn - γ并下调IL-4、IL-5和IL-13的产生，而CXCL4下调ifn - γ并上调TH2细胞因子。在多克隆激活的纯初始CD4+ T细胞上也观察到类似的效果。CXCL10和CXCL4对TH1和TH2细胞因子产生的相反作用被一种能够中和CXCR3-A和CXCR3-B的抗cxcr3抗体所抑制，这显然与不同信号转导途径的激活有关。此外，CXCL10上调T细胞中表达的T-box mRNA水平，下调GATA-3表达，而CXCL4下调T细胞中表达的T-box mRNA水平，上调GATA-3表达。最后，CXCL4而非CXCL10诱导IL-5和IL-13启动子的直接激活。结论：CXCL10和CXCL4对人TH1和TH2细胞因子的产生发挥相反的作用，可能是通过各自与CXCR3-A或CXCR3-B相互作用，进而激活不同的信号转导途径。这可能代表了T-H细胞反应的内部调节途径，并可能有助于调节慢性炎症反应，包括过敏。
Background: Two variants of the CXCR3 receptor exist, one (CXCR3-A) reactive with CXCL9, CXCL10, and CXCL11 and the other (CXCR3-B) also reactive with CXCL4. Both variants are contemporarily expressed by human T cells.Objective: We sought to investigate the in vitro effects of CXCL10 and CXCL4 on the production of T(H)1 or T(H)2 cytokines.Methods: The cytokine profile of antigen-specific human CD4(+) T-cell lines obtained in the absence or presence of CXCL10 or CXCL4 was evaluated by means of quantitative RT-PCR, flow cytometry, and ELISA.Results: CXCL10 upregulated IFN-gamma and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-gamma and upregulated TH2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4+ T cells. The opposite effects of CXCL10 and CXCL4 on TH1 and TH2 cytokine production were inhibited by an anti-CXCR3 antibody able to neutralize both CXCR3-A and CXCR3-B and were apparently related to the activation of distinct signal transduction pathways. Moreover, CXCL10 upregulated mRNA levels of T-box expressed in T cells and downregulated GATA-3 expression, whereas CXCL4 downregulated T-box expressed in T cells and upregulated GATA-3. Finally, CXCL4, but not CXCL10, induced direct activation of IL-5 and IL-13 promoters.Conclusion: CXCL10 and CXCL4 exert opposite effects on the production of human TH1 and TH2 cytokines, likely through their respective interaction with CXCR3-A or CXCR3-B and the consequent activation of different signal transduction pathways. This might represent an internal regulatory pathway of T-H cell responses and might contribute to the modulation of chronic inflammatory reactions, including allergy.