Regulatory role of antigen-induced interleukin-10, produced by CD4+ T cells, in airway neutrophilia in a murine model for asthma
Regulatory role of antigen-induced interleukin-10, produced by CD4+ T cells, in airway neutrophilia in a murine model for asthma
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DOI：
10.1016/j.ejphar.2011.12.020
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发表时间：
2012-02-29
影响因子：
5
通讯作者：
Chaplin, David D.
中科院分区：
文献类型：
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作者：
Nabe, Takeshi;Ikedo, Ayumu;Chaplin, David D.
有研究表明，白细胞介素(IL)-10主要通过抑制Th2细胞介导的嗜酸性气道炎症对包括哮喘在内的变应性炎症发挥免疫抑制作用。在致敏小鼠气道内多次抗原刺激的实验性哮喘模型中，多重刺激诱导了IL-10的产生以及肺内嗜酸性粒细胞和中性粒细胞的增加。在本研究中，我们利用抗IL-10受体单克隆抗体揭示了内源性产生IL-10的细胞来源，以及IL-10在气道白细胞炎症中的作用。先用卵清蛋白+ Al（OH）致敏Balb/c小鼠(3)，然后气管内给卵清蛋白致敏4次。流式细胞术分析显示，IL-10的细胞来源是缺乏转录因子叉头盒P3的CD4(+) T细胞。在第4次刺激前使用抗il -10受体单克隆抗体显著增加气道中性粒细胞以及IL-1 β、CXC趋化因子、角化细胞衍生趋化因子（KC）和巨噬细胞炎症蛋白(MIP)-2的产生，但不增加气道嗜酸性粒细胞、Th2细胞因子（IL-4和IL-5）的产生，或后期特异性气道抵抗的增加。大约40%的IL-10受体（+）细胞表达巨噬细胞标志物F4/80，而只有3-4%的IL-10受体（+）细胞是粒细胞分化抗原(Gr)-1（高）细胞（中性粒细胞）。综上所述，多次气道抗原刺激诱导表达il -10的CD4(+) T细胞增殖调节气道中性粒细胞。IL-10功能的全身阻断与IL-1 β和CXC趋化因子的增加相一致。因此，IL-1 β和CXC趋化因子可能是开发中性粒细胞哮喘新药物治疗的靶点。(C) 2011 Elsevier B.V.版权所有
It has been suggested that interleukin (IL)-10 exerts immunosuppressive effects on allergic inflammation, including asthma, mainly through inhibition of Th2 cell-mediated eosinophilic airway inflammation. In a model of experimental asthma utilizing multiple intratracheal antigen challenges in sensitized mice, IL-10 production as well as eosinophilia and neutrophilia in the lung were induced by the multiple challenges. In this study, we set out to reveal the cellular source of endogenously produced IL-10, and the roles of IL-10 in airway leukocyte inflammation using an anti-IL-10 receptor monoclonal antibody. Balb/c mice were sensitized i.p. with ovalbumin+ Al(OH)(3), and then challenged by intratracheal administration of ovalbumin 4 times. Flow cytometric analyses revealed that the cellular source of IL-10 was CD4(+) T cells lacking the transcription factor, forkhead box P3. Treatment with anti-IL-10 receptor monoclonal antibody prior to the 4th challenge significantly augmented airway neutrophilia as well as the production of IL-1 beta, and CXC chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2, but not airway eosinophilia, Th2 cytokine (IL-4 and IL-5) production, or a late-phase increase in specific airway resistance. Approximately 40% of IL-10 receptor(+) cells expressed the macrophage marker F4/80, whereas only 3-4% of the IL-10 receptor(+) cells were granulocyte differentiation antigen (Gr)-1(high) cells (neutrophils). In conclusion, multiple airway antigen challenges induced the proliferation of IL-10-expressing CD4(+) T cells in regulating airway neutrophilia. Systemic blockade of IL-10 function coincided with increases in IL-1 beta and CXC chemokines. Thus, IL-1 beta and CXC chemokines may be targets for development of novel pharmacotherapy for neutrophilic asthma. (C) 2011 Elsevier B.V. All rights reserved.