Exp Mol Med.  2008 Apr;40(2):167-175. 10.3858/emm.2008.40.2.167.

TNF-alpha-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells

• Kim H
• Hwang JS
• Woo CH
• Kim EY
• Kim TH
• Cho KJ
• Kim JH
• Seo JM
• Lee SS

• KMID: 1052939
• DOI: http://doi.org/10.3858/emm.2008.40.2.167

Abstract

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-alpha 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-alpha in A549 cells, suggesting a potential role of ROS in the TNF-alpha-induced signaling to ICAM-1 expression and monocyte adhesion to airway epithelium. Further, we found out that expression of Rac(N17), a dominant negative mutant of Rac1, suppressed TNF-alpha-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-alpha-induced signaling to ICAM-1 expression in airway epithelium. Finally, pretreatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kappaB, reduced TNF-alpha-induced ICAM-1 expression and both DPI and Rac(N17) significantly diminished NF-kappaB activation in response to TNF-alpha. Together, we propose that Rac1-ROS-linked cascade mediate TNF-alpha-induced ICAM-1 up-regulation in the airway epithelium via NF-kappaB-dependent manner.

Keyword

intercellular adhesion molecule-1; NF-kappaB; rac GTP-binding proteins; reactive oxygen species; respiratory mucosa; tumor necrosis factor-alpha

MeSH Terms

Cell Line
Electrophoresis, Polyacrylamide Gel
Epithelial Cells/metabolism
Humans
Intercellular Adhesion Molecule-1/*physiology
Microscopy, Confocal
Trachea/cytology/*metabolism
Tumor Necrosis Factor-alpha/*physiology
Up-Regulation/*physiology
rac GTP-Binding Proteins/*metabolism