TNF-alpha-induced up-regulation of intercellular adhesion molecule-1 is regulated by a Rac-ROS-dependent cascade in human airway epithelial cells.
10.3858/emm.2008.40.2.167
- Author:
Hyunju KIM
1
;
Jung Sun HWANG
;
Chang Hoon WOO
;
Eun Young KIM
;
Tae Hee KIM
;
Kyung Jin CHO
;
Jae Hong KIM
;
Ji Min SEO
;
Sang Soo LEE
Author Information
1. School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Korea. otalhip@hallym.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
intercellular adhesion molecule-1;
NF-kappaB;
rac GTP-binding proteins;
reactive oxygen species;
respiratory mucosa;
tumor necrosis factor-alpha
- MeSH:
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
- From:Experimental & Molecular Medicine
2008;40(2):167-175
- CountryRepublic of Korea
- Language:English
-
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.
