Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells

O'Connell, Maria A. ORCID: https://orcid.org/0000-0002-0267-0951, Bennett, Brydon L., Mercurio, Frank, Manning, Anthony M. and Mackman, Nigel (1998) Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. Journal of Biological Chemistry, 273 (46). pp. 30410-30414. ISSN 0021-9258

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Abstract

Mononuclear phagocytes play a major role in immune and inflammatory responses. Bacterial lipopolysaccharide (LPS) induces monocytes to express a variety of genes by activating the NF-kappaB/Rel transcription factor family. Recently, we have reported that the tumor necrosis factor and interleukin 1 signaling pathways activate two kinases, IKK1 and IKK2. Phosphorylation of the IkappaB cytoplasmic inhibitors, IkappaBalpha, IkappaBbeta, and IkappaBepsilon, by these kinases triggers proteolytic degradation and the release of NF-kappaB/Rel proteins into the nucleus. At present, the role of the IKKs in LPS signaling has not been investigated. Here, we report that LPS induces IKK activity in human monocytes and THP-1 monocytic cells. The kinetics of activation of kinase activity in monocytic cells are relatively slow with maximal activity observed at 60 min, which coincides with the degradation of IkappaBs and the nuclear translocation of NF-kappaB. In transfection experiments, overexpression of wild type IKK1, a dominant negative mutant IKK1 (K44M), or wild type IKK2 did not affect LPS-induced kappaB-dependent transcription in monocytic cells. In contrast, a dominant negative mutant of IKK2 inhibited LPS induction of kappaB-dependent transcription in a dose-dependent manner. These results indicate that LPS induction of kappaB-dependent gene expression in human monocytic cells requires activation of IKK2.

Item Type:	Article
Uncontrolled Keywords:	cell line,enzyme activation,humans,i-kappa b kinase,kinetics,lipopolysaccharides,monocytes,nf-kappa b,promoter regions, genetic,protein-serine-threonine kinases,signal transduction,tumor necrosis factor-alpha
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Pharmaceutical Cell Biology (former - to 2017) Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Depositing User:	Pure Connector
Date Deposited:	11 Jun 2014 13:08
Last Modified:	25 Sep 2024 11:13
URI:	https://ueaeprints.uea.ac.uk/id/eprint/48271
DOI:	10.1074/jbc.273.46.30410

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