tailieunhanh - Báo cáo khóa học: ICAM-1 expression is highly NF-jB-dependent in A549 cells No role for ERK and p38 MAPK

The transcription factor nuclear factorjB(NF-jB) 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 con-stitutively active dominant version of IjBa,IjBaDN, was introduced into A549 pulmonary cells by adenovirus-mediated delivery. The dominant IjB, but not a null viral vector, prevented the induction of NF-jB-dependent transcription by both tumor necrosis factora(TNFa)and interleukin-1b(IL-1b). . | Eur. J. Biochem. 271 785-791 2004 FEBS 2004 doi ICAM-1 expression is highly NF-jB-dependent in A549 cells No role for ERK and p38 MaPk Neil S. Holden1 Matthew C. Catley2 Lisa M. Cambridge2 Peter J. Barnes2 and Robert Newton1 1 Department of Biological Sciences University of Warwick Coventry UK 2Thoracic Medicine National Heart Lung Institute Imperial College Faculty of Medicine London UK The transcription factor nuclear factor kB NF-kB 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 IkB IkBoDN was introduced into A549 pulmonary cells by adenovirus-mediated delivery. The dominant IkB but not a null viral vector prevented the induction of NF-KB-dependent transcription by both tumor necrosis factor a TNFa and interleukin-1b IL-1b . Similarly both TNFa and IL-1b strongly induced mRNA and protein expression of intercellular adhesion molecule ICAM -1 and in each case this was prevented by adenovirus expressing the dominant IkB but not by the null virus thereby establishing ICAM-1 as an NF-KB-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-kB. 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 TNFa or IL-1 b-induced translocation and DNA binding of NF-kB. Furthermore these inhibitors showed no pharmacologically relevant effect on NF-KB-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-kB signalling pathway in pulmonary inflammatory diseases and suggest that inhibitors of the