Tanabe T, Shimokawaji T, Kanoh S, Rubin B K
Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Clin Exp Allergy. 2014 Apr;44(4):540-52. doi: 10.1111/cea.12283.
IL-13, a helper T cell type 2 (Th2) cytokine, transforms cultured airway epithelial cells to goblet cells, and this is not inhibited by corticosteroids. IL-33 stimulates Th2 cytokines and is highly expressed in airways of persons with asthma. The effect of IL-33 on goblet cell differentiation and cytokine secretion has not been described.
We examined the effect of IL-33 on CXCL8/IL-8 secretion from goblet or normally differentiated human bronchial epithelial (NHBE) cells and signalling pathways associated with IL-33 activation in these cells.
Normal human bronchial epithelial cells were grown to goblet or normally differentiated ciliated cell phenotype at air-liquid interface in the presence or absence of IL-13. After 14 days, differentiated cells were exposed to IL-33 for 24 h.
CXCL8/IL-8 secretion into the apical (air) side of the goblet cells was greater than from normally differentiated cells (P < 0.01), and IL-33 stimulated apical CXCL8/IL-8 release from goblet cells, but not from normally differentiated cells (P < 0.01). IL-33 increased ERK 1/2 phosphorylation in goblet cells (P < 0.05), and PD98059, a MAPK/ERK kinase inhibitor, attenuated IL-33-stimulated CXCL8/IL-8 secretion from goblet cells (P < 0.001). IL-13 induced ST2 mRNA (P < 0.02) and membrane-bound ST2 protein expression on the apical side surface of goblet cells compared with normally differentiated cells, and neutralization with anti-ST2R antibody attenuated IL-33-induced apical CXCL8/IL-8 secretion from goblet cells (P < 0.02).
Goblet cells secrete CXCL8/IL-8, and this is increased by IL-33 through ST2R-ERK pathway, suggesting a mechanism for enhanced airway inflammation in the asthmatic airway with goblet cell metaplasia.
白细胞介素-13（IL-13）是一种2型辅助性T细胞（Th2）细胞因子，可使培养的气道上皮细胞转化为杯状细胞，且这种转化不受皮质类固醇抑制。IL-33可刺激Th2细胞因子分泌，在哮喘患者气道中高表达。IL-33对杯状细胞分化和细胞因子分泌的影响尚未见报道。
我们研究了IL-33对杯状或正常分化的人支气管上皮（NHBE）细胞分泌CXCL8/IL-8的影响以及与这些细胞中IL-33激活相关的信号通路。
在有或无IL-13存在的情况下，将正常人支气管上皮细胞在气液界面培养成杯状或正常分化的纤毛细胞表型。14天后，将分化的细胞暴露于IL-33中24小时。
杯状细胞向顶端（空气）侧分泌CXCL8/IL-8的量大于正常分化细胞（P<0.01），IL-33刺激杯状细胞顶端CXCL8/IL-8释放，但对正常分化细胞无此作用（P<0.01）。IL-33增加杯状细胞中细胞外信号调节激酶1/2（ERK 1/2）的磷酸化（P<0.05），丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）激酶抑制剂PD98059可减弱IL-33刺激的杯状细胞CXCL8/IL-8分泌（P<0.001）。与正常分化细胞相比，IL-13诱导杯状细胞顶端表面ST2 mRNA表达（P<0.02）和膜结合ST2蛋白表达，用抗ST2R抗体中和可减弱IL-33诱导的杯状细胞顶端CXCL8/IL-8分泌（P<0.02）。
杯状细胞分泌CXCL8/IL-8，IL-33通过ST2R-ERK途径使其增加，提示杯状细胞化生的哮喘气道炎症增强的一种机制。
