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KMID : 0620920080400020167
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Experimental & Molecular Medicine
2008 Volume.40 No. 2 p.167 ~ p.175
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TNF-α-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells
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Kim Hyun-Ju
Seo Ji-Min
Kim Jae-Hong
Woo Chang-Hoon
Hwang Jung-Sun
Kim Eun-Young
Kim Tae-Hee
Cho Kyung-Jin
Lee Sang-Soo
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Abstract
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Up-regulation of intercellular adhesion molecule-1 (ICAM-1) in the lung airway epithelium is associated with the epithelium-leukocyte interaction, critical for the pathogenesis of various lung airway inflammatory diseases such as asthma. However, little is known about how ICAM-1 is up-regulated in human airway epithelial cells. In this study, we show that tumor TNF-α induces monocyte adhesion to A549 human lung airway epithelium and also up-regulation of ICAM-1 expression. These effects were significantly diminished by pre-treatment with diphenyliodonium (DPI), an inhibitor of NADPH oxidase-like flavoenzyme. In addition, the level of reactive oxygen species (ROS) was increased in response to TNF-α in A549 cells, suggesting a potential role of ROS in the TNF-α-induced signaling to ICAM-1 expression and monocyte adhesion to airway epithelium. Further, we found out that expression of RacN17, a dominant negative mutant of Rac1, suppressed TNF-α-induced ROS generation, ICAM-1 expression, and monocyte adhesion to airway epithelium. These findings suggest that Rac1 lies upstream of ROS generation in the TNF-α-induced signaling to ICAM-1 expression in airway epithelium. Finally, pretreatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, reduced TNF-α-induced ICAM-1 expression and both DPI and RacN17 significantly diminished NF-κB activation in response to TNF-α. Together, we propose that Rac1-ROS-linked cascade mediate TNF-α-induced ICAM-1 up-regulation in the airway epithelium via NF-κB-dependent manner.
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KEYWORD
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intercellular adhesion molecule-1, NFκ B, rac GTP-binding proteins, reactive oxygen species, respiratory mucosa, tumor necrosis factor-α
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