title: TNF-alpha-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells.
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 RacN17, 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 RacN17 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.
authors.affiliation: School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea.
authors.forename: Hyunju
authors.initials: H
authors.lastname: Kim
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Hwang
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Tae Hee
authors.initials: TH
authors.lastname: Kim
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Cho
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Kim
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Seo
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Lee
mesh_terms: D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology*; D018613:Microscopy, Confocal; D014132:Trachea / Q000166:cytology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D020744:rac GTP-Binding Proteins