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

Hyunju Kim, Jung Sun Hwang, Chang Hoon Woo, Eun Young Kim, Tae Hee Kim, Kyung Jin Cho, Ji Min Seo, Sang Soo Lee, Jae-Hong Kim

Research output: Contribution to journalArticle

50 Citations (Scopus)

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-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.

Original languageEnglish
Pages (from-to)167-175
Number of pages9
JournalExperimental and Molecular Medicine
Volume40
Issue number2
DOIs
Publication statusPublished - 2008 Apr 30

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Keywords

  • Intercellular adhesion molecule-1
  • NF-κB
  • Rac GTP-binding proteins
  • Reactive oxygen species
  • Respiratory mucosa
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Biochemistry
  • Genetics

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