Department of Respiratory Medicine, Changzheng Hospital, Second Military Medical University, Shanghai 200003, People's Republic of China.
J Immunol. 2013 Jan 1;190(1):438-46. doi: 10.4049/jimmunol.1201827. Epub 2012 Nov 28.
Recently, the serum levels of YKL-40, a chitinase-like glycoprotein, have been shown to be significantly elevated in asthmatics and are associated with asthma severity. Although these studies raise the possibility that YKL-40 may influence asthma, the mechanisms remain unknown. This study firstly investigated the mechanisms involved in YKL-40-mediated inflammation in human bronchial epithelial cells (HBECs) and analyzed the soluble factors secreted by bronchial epithelial cells exposed to YKL-40 that were responsible for increasing proliferation and migration of primary normal human bronchial smooth muscle cells (BSMCs). YKL-40-induced inflammation was assayed in two HBECs (BEAS-2B cell line and primary HBECs). In addition, we treated BEAS-2B cells and HBECs with YKL-40 and added the conditioned culture media to BSMCs. The proliferation and migration of BSMCs were determined by premixed WST-1 cell proliferation reagent (Clontech Laboratories) and QCM chemotaxis migration assay (Millipore), respectively. Bronchial epithelial cells treated with YKL-40 resulted in a significant increase of IL-8 production, which was dependent on MAPK (JNK and ERK) and NF-κB pathways activation. YKL-40-induced IL-8 was found to further stimulate proliferation and migration of BSMCs, and the effects were inhibited after neutralizing IL-8. Through investigating the interaction of airway epithelium and smooth muscle, our findings implicate that YKL-40 may be involved in the inflammation of asthma by induction of IL-8 from epithelium, subsequently contributing to BSMC proliferation and migration. Moreover, inhibition of IL-8 signaling is a potential therapeutic target for YKL-40-induced inflammation and remodeling of asthma.
最近，壳聚糖酶样糖蛋白 YKL-40 的血清水平在哮喘患者中显著升高，并且与哮喘的严重程度相关。虽然这些研究提出了 YKL-40 可能影响哮喘的可能性，但机制尚不清楚。本研究首先研究了 YKL-40 介导的人支气管上皮细胞（HBEC）炎症的机制，并分析了暴露于 YKL-40 的支气管上皮细胞分泌的可溶性因子，这些因子负责增加原代正常人支气管平滑肌细胞（BSMC）的增殖和迁移。在两种 HBEC（BEAS-2B 细胞系和原代 HBEC）中测定了 YKL-40 诱导的炎症。此外，我们用 YKL-40 处理 BEAS-2B 细胞和 HBEC，并将条件培养基添加到 BSMC 中。通过预混 WST-1 细胞增殖试剂（Clontech Laboratories）和 QCM 趋化迁移测定（Millipore）分别测定 BSMC 的增殖和迁移。用 YKL-40 处理的支气管上皮细胞导致 IL-8 产生显著增加，这依赖于 MAPK（JNK 和 ERK）和 NF-κB 途径的激活。发现 YKL-40 诱导的 IL-8 进一步刺激 BSMC 的增殖和迁移，并且在用 IL-8 中和后抑制了这些作用。通过研究气道上皮和平滑肌之间的相互作用，我们的发现表明 YKL-40 可能通过诱导上皮细胞产生 IL-8 参与哮喘的炎症，进而导致 BSMC 的增殖和迁移。此外，抑制 IL-8 信号转导是治疗 YKL-40 诱导的哮喘炎症和重塑的潜在靶点。
