Molecular mechanisms of chemokine gene expression in allergic airway inflammation : Selective induction of eotaxin and TARC by Th2 cytokines in airway epithelial cells

呼吸道上皮细胞驱动的趋化因子被认为在过敏性呼吸道炎症性疾病如哮喘的发病机制中发挥重要作用。然而，目前尚不清楚某些趋化因子如何在这种呼吸道炎症中起主导作用；例如，哮喘中的嗜酸性粒细胞和慢性支气管炎中的中性粒细胞。我们研究了Th-2型细胞因子IL-4和IL-13在选择性上调气道上皮细胞趋化因子基因表达中的作用。我们发现IL-4和IL-13都能刺激嗜酸性粒细胞基因的表达，这被认为是嗜酸性粒细胞在呼吸道中募集的关键。相反，这些Th2细胞因子下调IL-8基因的表达，而IL-8是众所周知的一种强大的中性粒细胞趋化因子。此外，IL-13明显诱导STAT6的激活，这是嗜酸性粒细胞趋化蛋白转录的重要步骤，但下调了NF-κB的转录。哮喘患者在知情同意后获得的呼吸道上皮细胞，往往比正常和支气管炎患者的气道上皮细胞产生更多的嗜酸性粒细胞趋化因子。这些观察结果表明，Th2细胞因子在变态反应性呼吸道炎症中选择性诱导某些趋化因子可能起重要作用。

Airway epithelium-drived chemokines are believed to play important roles in the pathogenesis of allergic airway inflammatory diseases such as bronchial asthma. However, it remains unclear how certain chemokines are predominant in such airway inflammation ; for example, eosinophils in asthma and neutrophils in chrnic bronchitis, respectively. We studied the effect of Th-2 type cytokines such as IL-4 and IL-13 in the selective upregulation in chemokine gene expression in airway epithelial cells. We found that IL-4 and IL-13 both stimulated eotaxin gene expression, which is considered to be crucial in eosinophil recruitment in the airways. In contrast, these Th2 cytokines downregulated IL-8 gene expression, which is well known to be a potent neutrophil chemoattaractant. Further, IL-13 clearly induced STAT6 activation, an important step for the eotaxin transcription, but downregulated NFκB transcativation. Airway epithelial cells harvested from asthmatic subjects after informed consent, tended to show more eotaxin production than those from normal and bronchitis patients. These observations demonstrated that Th2 cytokines may play an important role in the selective induction of certain chemokines in allergic airway inflmmation.