TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells
TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells
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DOI：
10.4049/jimmunol.179.2.1080
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发表时间：
2007-07-15
影响因子：
4.4
通讯作者：
Schleimer, Robert P.
中科院分区：
文献类型：
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作者：
Kato, Atsushi;Favoreto, Silvio, Jr.;Schleimer, Robert P.
胸腺间质淋巴生成素(TSLP)在哮喘中升高，并触发树突状细胞介导的Th2炎症反应。尽管已证明TSLP主要由呼吸道上皮细胞产生，但对上皮性TSLP表达的调节尚未得到广泛研究。我们研究了TSLP在细胞因子或TLR配体处理的正常人支气管上皮细胞(NHBE)中的表达。IL-4(5.5倍)和IL-13(5.3倍)可显著上调NHBE中TSLP的mRNA表达，而肿瘤坏死因子-α、转化生长因子-γ和干扰素-β对其表达有微弱上调作用，而干扰素-γ对其无明显影响。在被测试的TLR配体中，只有TLR3配体(DsRNA)显著上调了TSLP mRNA的表达(66.8倍)。鼻病毒体外感染也可诱发TSLP。DsRNA(120+/-23pg/ml)刺激后可检测到TSLP蛋白的表达。联合应用肿瘤坏死因子-α和白介素4可产生可检测到的TSLP蛋白水平(4013pg/ml)。此外，IL-4和dsRNA(mRNA；207倍，蛋白质；325+/-75pg/ml)联合应用可协同增强TSLP。一项关于小干扰RNA的研究表明，dsRNA诱导TSLP的作用依赖于通过TLR3传递的核因子-KB和干扰素调节因子3(IRF-3)信号。外用强效糖皮质激素丙酸氟替卡松显著抑制NHBE中依赖dsRNA的TSLP的产生。这些结果表明，TLR3配体和Th2细胞因子刺激可诱导气道上皮细胞表达TSLP，糖皮质激素治疗可抑制这种反应。这表明呼吸道病毒感染和Th2细胞因子产生细胞的募集可能通过诱导哮喘气道中的TSLP而放大Th2炎症。
Thymic stromal lymphopoietin (TSLP) is elevated in asthma and triggers dendritic cell-mediated activation of Th2 inflammatory responses. Although TSLP has been shown to be produced mainly by airway epithelial cells, the regulation of epithelial TSLP expression has not been extensively studied. We investigated the expression of TSLP in cytokine- or TLR ligand-treated normal human bronchial epithelial cells (NHBE). The mRNA for TSLP was significantly up-regulated by stimulation with IL-4 (5.5-fold) and IL-13 (5.3-fold), weakly up-regulated by TNF-alpha, TGF-gamma, and IFN-beta, and not affected by IFN-gamma in NHBE. TSLP mRNA was only significantly up-regulated by the TLR3 ligand (dsRNA) among the TLR ligands tested (66.8-fold). TSLP was also induced by in vitro infection with rhinovirus. TSLP protein was detected after stimulation with dsRNA (120 +/- 23 pg/ml). The combination of TNF-a and IL-4 produced detectable levels of TSLP protein (40 13 pg/ml). In addition, TSLP was synergistically enhanced by a combination of IL-4 and dsRNA (mRNA; 207-fold, protein; 325 +/- 75 pg/ml). The induction of TSLP by dsRNA was dependent upon NF-KB and IFN regulatory factor 3 (IRF-3) signaling via TLR3 as indicated by a study with small interfering RNA. The potent topical glucocorticoid fluticasone propionate significantly suppressed dsRNA-dependent TSLP production in NHBE. These results suggest that the expression of TSLP is induced in airway epithelial cells by stimulation with the TLR3 ligand and Th2 cytokines and that this response is suppressed by glucocorticoid treatment. This implies that respiratory viral infection and the recruitment of Th2 cytokine producing cells may amplify Th2 inflammation via the induction of TSLP in the asthmatic airway.