IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway
IL-13-induced Clara cell secretory protein expression in airway epithelium: role of EGFR signaling pathway
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DOI：
10.1152/ajplung.00404.2001
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发表时间：
2002-07-01
影响因子：
4.9
通讯作者：
Nadel, JA
中科院分区：
文献类型：
--
作者：
Kim, S;Shim, JJ;Nadel, JA
以前的工作表明，Th 2细胞因子白细胞介素（IL）-13诱导杯状细胞化生通过间接机制，涉及表皮生长因子受体（EGFR）的表达和随后的激活。由于克拉拉细胞分泌蛋白（CCSP）的表达已被报道在表达粘蛋白的细胞中，我们研究了IL-13对无病原体大鼠气道和肺粘液表皮样NCI-H292细胞中CCSP基因和蛋白表达的影响。鼻腔内滴注IL-13可在8-16 h内诱导无纤毛上皮细胞中CCSP mRNA的表达，24 - 48 h达到最大值; CCSP免疫染色呈时间依赖性增加，48 h达到最大值。CCSP免疫组化染色定位于非颗粒状分泌细胞、杯状细胞和管腔内。用选择性EGFR酪氨酸激酶抑制剂BIBX 1522、环磷酰胺（骨髓白细胞动员抑制剂）或IL-8阻断抗体预处理可阻止CCSP染色。用EGFR配体转化生长因子-α处理NCI-H292细胞，而不是单独用IL-13处理，诱导CCSP基因和蛋白质表达。选择性EGFR酪氨酸激酶抑制剂BIBX 1522和AG 1478可阻止NCI-H292细胞中CCSP的表达，但血小板衍生生长因子受体酪氨酸激酶抑制剂AG 1295无作用。这些发现表明IL-13通过EGFR和白细胞依赖性途径诱导CCSP表达。
Previous work showed that the Th2 cytokine interleukin (IL)-13 induces goblet cell metaplasia via an indirect mechanism involving the expression and subsequent activation of epidermal growth factor receptor (EGFR). Because Clara cell secretory protein (CCSP) expression has been reported in cells that express mucins, we examined the effect of IL-13 on CCSP gene and protein expression in pathogen-free rat airways and in pulmonary mucoepidermoid NCI-H292 cells. Intratracheal instillation of IL-13 induced CCSP mRNA in epithelial cells without cilia within 8-16 h, maximal between 24 and 48 h; CCSP immunostaining increased in a time-dependent fashion, maximal at 48 h. The CCSP immunostaining was localized in nongranulated secretory cells and goblet cells and in the lumen. Pretreatment with the selective EGFR tyrosine kinase inhibitor BIBX1522, cyclophosphamide (an inhibitor of bone marrow leukocyte mobilization), or a blocking antibody to IL-8 prevented CCSP staining. Treatment of NCI-H292 cells with the EGFR ligand transforming growth factor-alpha, but not with IL-13 alone, induced CCSP gene and protein expression. Selective EGFR tyrosine kinase inhibitors, BIBX1522 and AG1478, prevented CCSP expression in NCI-H292 cells, but the platelet-derived growth factor receptor tyrosine kinase inhibitor AG1295 had no effect. These findings indicate that IL-13 induces CCSP expression via an EGFR- and leukocyte-dependent pathway.