PM 2.5 -induced oxidative stress increases intercellular adhesion molecule-1 expression in lung epithelial cells through
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RESEARCH
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PM2.5-induced oxidative stress increases intercellular adhesion molecule-1 expression in lung epithelial cells through the IL-6/AKT/STAT3/NF-κB-dependent pathway Chen-Wei Liu1, Tzu-Lin Lee1†, Yu-Chen Chen1†, Chan-Jung Liang2,3, Shu-Huei Wang1, June-Horng Lue1, Jaw-Shiun Tsai4,5, Shih-Wei Lee6, Shun-Hua Chen7, Yi-Fan Yang8, Tzu-Yi Chuang6,8* and Yuh-Lien Chen1*
Abstract Background: Epidemiological studies have shown that ambient air pollution is closely associated with increased respiratory inflammation and decreased lung function. Particulate matters (PMs) are major components of air pollution that damages lung cells. However, the mechanisms remain to be elucidated. This study examines the effects of PMs on intercellular adhesion molecule-1 (ICAM-1) expression and the related mechanisms in vitro and in vivo. Result: The cytotoxicity, reactive oxygen species (ROS) generation, and monocyte adherence to A549 cells were more severely affected by treatment with O-PMs (organic solvent-extractable fraction of SRM1649b) than with W-PMs (water-soluble fraction of SRM1649b). We observed a significant increase in ICAM-1 expression by O-PMs, but not W-PMs. O-PMs also induced the phosphorylation of AKT, p65, and STAT3. Pretreating A549 cells with N-acetyl cysteine (NAC), an antioxidant, attenuated O-PMs-induced ROS generation, the phosphorylation of the mentioned kinases, and the expression of ICAM-1. Furthermore, an AKT inhibitor (LY294002), NF-κB inhibitor (BAY11–7082), and STAT3 inhibitor (Stattic) significantly down-regulated O-PMs-induced ICAM-1 expression as well as the adhesion of U937 cells to epithelial cells. Interleukin-6 (IL-6) was the most significantly changed cytokine in O-PMs-treated A549 cells according to the analysis of the cytokine antibody array. The IL-6 receptor inhibitor tocilizumab (TCZ) and small interfering RNA for IL-6 significantly reduced ICAM-1 secretion and expression as well as the reduction of the AKT, p65, and STAT3 phosphorylation in O-PMs-treated A549 cells. In addition, the intratracheal instillation of PMs significantly increased the levels of the ICAM-1 and IL-6 in lung tissues and plasma in WT mice, but not in IL-6 knockout mice. Pre-administration of NAC attenuated those PMs-induced adverse effects in WT mice. Furthermore, patients with chronic obstructive pulmonary disease (COPD) had higher plasma levels of ICAM-1 and IL-6 compared to healthy subjects. Conclusion: These results suggest that PMs increase ICAM-1 expression in pulmonary epithelial cells in vitro and in vivo through the IL-6/AKT/STAT3/NF-κB signaling pathway. Keywords: Particulate matters (PMs), Intercellular adhesion molecule-1 (ICAM-1), Reactive oxygen species (ROS), Interleukin-6 (IL-6), Inflammation
* Correspondence: [email protected]; [email protected] † Equal contributors 6 Department of Internal Medicine, Taoyuan General Hospital, Department of Health and Welfare, No.1492, Zhongshan Road, Taoyuan, Taiwan 1 Department of Anatomy and Cell Biology, College of Medicine, National Taiwan U
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