Heijink Irene H, Marcel Kies P, van Oosterhout Antoon J M, Postma Dirkje S, Kauffman Henk F, Vellenga Edo
Department of Allergology, Pulmonology, and Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, NL-9713 GZ, Groningen, The Netherlands.
Am J Respir Cell Mol Biol. 2007 Mar;36(3):351-9. doi: 10.1165/rcmb.2006-0160OC. Epub 2006 Oct 5.
Thymus and Activation-Regulated Chemokine (TARC) may be critical in Th2 cell recruitment in allergic inflammation; however, the mechanisms of allergen-induced TARC release are unclear. Since airway epithelium is the first line of defense to inhaled allergens, we questioned whether house dust mite allergen (Der p) can induce TARC expression in bronchial epithelial cells, how this is regulated at the molecular level, and if micro-environmental cytokines augment this effect. We examined the effects of Der p and the cytokines IL-4 and TGF-beta on TARC expression in 16HBE cells and primary bronchial asthma epithelium. Real-time PCR and immunofluorescence demonstrated that Der p induces TARC expression in bronchial epithelium. Supernatants from Der p-stimulated 16HBE cells were able to induce TARC-dependent T cell trafficking. IL-4 and TGF-beta cooperatively enhanced Der p-induced TARC expression in 16HBE cells. Specific inhibitors, immunodetection, and gel-shifts revealed that these effects are mediated by phosphorylation of the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK) signaling and subsequent nuclear factor (NF)-kappaB activation. A Disintegrin And Metalloproteinase (ADAM), a family of proteins involved in shedding of various growth factors, was shown to be responsible for EGFR activation. The increase in TARC production by direct interaction of Der p with the bronchial epithelium may be an important initial step in the generation of allergic inflammation, which is further potentiated by micro-environmental cytokines. Interference with ADAM or EGFR activity may be a novel promising target to prevent TARC release and subsequent allergic inflammation.
胸腺与活化调节趋化因子（TARC）在过敏性炎症中Th2细胞募集过程中可能起关键作用；然而，变应原诱导TARC释放的机制尚不清楚。由于气道上皮是抵御吸入性变应原的第一道防线，我们不禁要问，屋尘螨变应原（Der p）是否能诱导支气管上皮细胞表达TARC，在分子水平上其如何被调控，以及微环境细胞因子是否会增强这种效应。我们研究了Der p以及细胞因子白细胞介素-4（IL-4）和转化生长因子-β（TGF-β）对16HBE细胞和原发性支气管哮喘上皮细胞中TARC表达的影响。实时聚合酶链反应（PCR）和免疫荧光显示，Der p可诱导支气管上皮细胞表达TARC。Der p刺激的16HBE细胞培养上清液能够诱导TARC依赖的T细胞迁移。IL-4和TGF-β协同增强Der p诱导的16HBE细胞中TARC的表达。特异性抑制剂、免疫检测和凝胶迁移实验表明，这些效应是由表皮生长因子受体（EGFR）磷酸化、丝裂原活化蛋白激酶（MAPK）信号传导以及随后的核因子-κB（NF-κB）激活介导的。一种参与多种生长因子脱落的蛋白质家族——解整合素和金属蛋白酶（ADAM），被证明与EGFR激活有关。Der p与支气管上皮细胞直接相互作用导致TARC产生增加，这可能是过敏性炎症发生的一个重要起始步骤，微环境细胞因子可进一步增强此效应。干扰ADAM或EGFR活性可能是预防TARC释放及后续过敏性炎症的一个新的有前景的靶点。
