ICAM‐1 expression is highly NF‐κB‐dependent in A549 cells

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Abstract
The transcription factor nuclear factor κB (NF-κB) is an activator of multiple cytokines, chemokines and adhesion molecules, which are important in inflammatory diseases such as asthma, and is consequently considered as an attractive therapeutic target. In the present study, a constitutively active dominant version of IκBα, IκBαDN, was introduced into A549 pulmonary cells by adenovirus-mediated delivery. The dominant IκB, but not a null viral vector, prevented the induction of NF-κB-dependent transcription by both tumor necrosis factor α (TNFα) and interleukin-1β (IL-1β). Similarly, both TNFα and IL-1β strongly induced mRNA and protein expression of intercellular adhesion molecule (ICAM)-1 and in each case this was prevented by adenovirus expressing the dominant IκB, but not by the null virus, thereby establishing ICAM-1 as an NF-κB-dependent gene. Numerous studies have suggested key roles for the p38 and extracellular regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascades in the activation and transactivation of NF-κB. We show here that SB203580, a selective inhibitor of the p38 MAPK, and PD098059 and UO126, both selective inhibitors of the ERK MAPK cascade, have no effect on TNFα or IL-1β-induced translocation and DNA binding of NF-κB. Furthermore, these inhibitors showed no pharmacologically relevant effect on NF-κB-dependent transcription nor was there any effect on expression of ICAM-1. Taken together these data highlight the potential use of inhibition of the NF-κB signalling pathway in pulmonary inflammatory diseases and suggest that inhibitors of the p38 and ERK MAPK pathways may be of lesser effect.

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