Dissociation of T helper type 2 cytokine-dependent airway lesions from signal transducer and activator of transcription 6 signalling in experimental chronic asthma
Dissociation of T helper type 2 cytokine-dependent airway lesions from signal transducer and activator of transcription 6 signalling in experimental chronic asthma
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DOI：
10.1046/j.1365-2222.2003.01647.x
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发表时间：
2003-05-01
影响因子：
6.1
通讯作者：
Kumar, RK
中科院分区：
文献类型：
--
作者：
Foster, PS;Webb, DC;Kumar, RK
背景2型辅助性T淋巴细胞（Th2细胞）及其细胞因子产物在哮喘发病中起重要作用。目的探讨Th2细胞因子信号通路中信号转导和转录激活因子（STAT） 6通路在慢性哮喘病变发生中的作用。方法对卵清蛋白致敏BALB/c小鼠长期吸入低质量浓度抗原致敏6周。采用组织形态学和免疫组化方法比较野生型小鼠与stat6缺陷小鼠和IL-4/13双缺陷小鼠气道病变。采用全身容积描记术评估气道对甲胆碱的反应。采用酶免疫法测定支气管周围淋巴结细胞产生细胞因子的数量。结果STAT6-/-小鼠发生了多种气道病变，至少与野生型小鼠相当，包括上皮内嗜酸性粒细胞和固有层慢性炎症细胞的积累，上皮下纤维化和上皮增厚。此外，与野生型动物相比，STAT6-/-小鼠表现出夸大的气道高反应性（AHR）。尽管炎性浸润和粘液细胞增生/化生减少的浆细胞产生的免疫球蛋白从Th2模式转变为Th1模式，同时支气管周围淋巴结细胞产生的ifn - γ增加，这与缺乏通过STAT6途径的信号传导一致。相比之下，基因靶向的IL-4/13-/-小鼠表现出明显减少的嗜酸性粒细胞募集和气道重塑，以及AHR的缺失。在该模型中，STAT6缺乏的作用与变应性支气管肺炎症模型中描述的炎症和AHR的抑制作用形成鲜明对比。这些结果提供了慢性哮喘吸入性激发模型中stat6独立AHR的证据，强调了IL-4和IL-13的关键效应作用，以及需要使用适当的模型来了解可能成为哮喘潜在治疗靶点的细胞因子信号通路。
Background Type 2 T helper lymphocytes (Th2 cells) and their cytokine products are important in the pathogenesis of asthma.Objective To examine the contribution of the signal transducer and activator of transcription (STAT) 6 pathway, involved in Th2 cytokine signalling, to the development of lesions of chronic asthma.Methods BALB/c mice sensitized to ovalbumin were chronically challenged by inhalational of low mass concentrations of antigen for 6 weeks. Airway lesions in wild-type mice were compared with those in STAT6-deficient mice and in IL-4/13 double-deficient mice by histomorphometry and immunohistochemistry. Airway responses to methacholine were evaluated by whole-body plethysmography. Cytokine production by peribronchial lymph node cells was quantified by enzyme immunoassay.Results STAT6-/- mice developed a variety of airway lesions that were at least equivalent to those in wild-type mice, including accumulation of intraepithelial eosinophils and of chronic inflammatory cells in the lamina propria, subepithelial fibrosis and epithelial thickening. In addition, STAT6-/- mice exhibited exaggerated airway hyper-reactivity (AHR) compared to wild-type animals. This was despite a shift from a Th2 to a Th1 pattern of immunoglobulin production by plasma cells in the inflammatory infiltrate and diminished mucous cell hyperplasia/metaplasia, together with increased production of IFN-gamma by peribronchial lymph node cells, consistent with absence of signalling via the STAT6 pathway. In contrast, gene-targeted IL-4/13-/- mice exhibited markedly diminished eosinophil recruitment and airway remodelling, as well as absence of AHR.Conclusions In this model, the effects of STAT6 deficiency were in marked contrast to the suppression of inflammation and AHR described in models of allergic bronchopulmonary inflammation. These results, which provide evidence of STAT6-independent AHR in an inhalational challenge model of chronic asthma, emphasize the critical effector roles of IL-4 and IL-13, as well as the need to use appropriate models to understand cytokine signalling pathways that may be potential therapeutic targets in asthma.