Mammalian target of rapamycin and p70S6K mediate thrombin-induced nuclear factor-κB activation and IL-8/CXCL8 release in human lung epithelial cells

被引：9

作者：

Lin, Chien-Huang ^{[1
]}

Shih, Chung-Hung ^{[2
,3
]}

Jiang, Chun-Ping ^{[1
]}

Wen, Heng-Ching ^{[2
]}

Cheng, Wun-Hao ^{[1
]}

Chen, Bing-Chang ^{[1
,2
,4
]}

机构：

[1] Taipei Med Univ, Coll Med, Grad Inst Med Sci, Taipei 110, Taiwan

[2] Taipei Med Univ, Coll Med, Sch Resp Therapy, 250 Wu Hsing St, Taipei 110, Taiwan

[3] Taipei Med Univ Hosp, Dept Internal Med, Div Pulm Med, Taipei, Taiwan

[4] Taipei Med Univ, Coll Med, Sch Med, Dept Internal Med, Taipei 110, Taiwan

来源：

EUROPEAN JOURNAL OF PHARMACOLOGY | 2020年 / 868卷

关键词：

Lung inflammation; Signalling pathway; Thrombin; Mammalian target of rapamycin; IL-8/CXCL8; IL-8; EXPRESSION; TISSUE-GROWTH; ACETYLATION; FIBROBLASTS; RECEPTOR; ASTHMA; MTOR; PHOSPHORYLATION; INTERLEUKIN-8; PROMOTES;

D O I：

10.1016/j.ejphar.2019.172879

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Thrombin plays a crucial role in lung inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD). Thrombin induces the release of interleukin-8 (IL-8)/CXCL8 by lung epithelial cells, and this phenomenon plays a vital role in lung inflammation. Our previous studies have indicated that thrombin stimulates IL-8/CXCL8 expression through PI3K/Akt/I kappa B kinase (IKK)alpha/beta/nuclear factor-kappa B (NF-kappa B) and p300 pathways in human lung epithelial cells. In the present study, we explored the roles of mammalian target of rapamycin (mTOR) and p70S6 kinase (p70S6K) in thrombin-induced NF-kappa B activation and IL-8/CXCL8 release in human lung epithelial cells. In this study, we found that rapamycin (an mTOR inhibitor) and p70S6K siRNA diminished thrombin-induced IL-8/CXCL8 release. Thrombin induced mTOR Ser2448 phosphorylation and p70S6K Thr389 phosphorylation in a time-dependent manner. Moreover, rapamycin attenuated thrombin-stimulated p70S6K phosphorylation. We also found that transfection of cells with the dominant negative mutant of Akt (Akt DN) reduced the thrombin-induced increase in mTOR phosphorylation and p70S6K phosphorylation. Moreover, thrombin-stimulated p300 phosphorylation was attenuated by Akt DN, rapamycin, and p70S6K siRNA. Thrombin triggered p70S6K translocation from the cytosol to the nucleus in a time-dependent manner. Thrombin induced the complex formation of p70S6K, p300, and p65; acetylation of p65 Lys310, and recruitment of p70S6K, p300, and p65 to the kappa B-binding site of the IL-8/CXCL8 promoter region. In conclusion, these results indicate that thrombin initiates the Akt-dependent mTOR/p70S6K signaling pathway to promote p300 phosphorylation and NF-kappa B activation and finally induces IL-8/CXCL8 release in human lung epithelial cells.

引用

页数：8