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

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.