title: Abrogation of NF-κB signaling in human neutrophils induces neutrophil survival through sustained p38-MAPK activation.
abstract: NF-κB, an important transcription factor in the regulation of cellular inflammation, is one of the prime targets for novel anti-inflammatory therapeutics. Nowadays, anti-inflammatory therapies rely mostly on steroids, which among other effects, inhibit NF-κB activity. However, steroids have only limited efficacy in the treatment on neutrophil-driven diseases, such as COPD. Human neutrophils play an important role in the pathogenesis of COPD, and clearance of these cells by apoptosis is an effective pathway for resolution of inflammation. In this study, we tested the hypothesis that modulation of the NF-κB pathway in human neutrophils affects survival. Importantly, the pharmacological NF-κB inhibitor Bay 11-7082 inhibited NF-κB signaling in human neutrophils as expected. However, we found that complete inhibition of NF-κB activity with 10 μM Bay 11-7082 prolonged neutrophil survival significantly, which was not observed with inhibitors for other signaling pathways. Bay 11-7082-induced neutrophil survival was dependent on p38-MAPK kinase activity, as the p38 kinase activity inhibitor SB203580 abrogated this response completely. Bay 11-7082 induced rapid and sustained p38 activation that correlated with inhibited NF-κB signaling and prolonged neutrophil survival. The precise role of NF-κB in regulation of p38-MAPK activation remains to be established. Under these conditions of survival, the stability of Bcl-xL but not Mcl-1 was enhanced. Although inhibition of NF-κB leads to down-regulation of inflammatory genes in many cell types, our results illustrate that interference with basal NF-κB signaling in neutrophils as a drug target should be used with caution.
authors.affiliation: Department of Respiratory Medicine, University Medical Center, Utrecht, The Netherlands.
authors.forename: Jeroen D
authors.initials: JD
authors.lastname: Langereis
authors.forename: Hanneke A J A
authors.initials: HA
authors.lastname: Raaijmakers
authors.forename: Laurien H
authors.initials: LH
authors.lastname: Ulfman
authors.forename: Leo
authors.initials: L
authors.lastname: Koenderman
mesh_terms: D015153:Blotting, Western; D002469:Cell Separation; D002470:Cell Survival; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013450:Sulfones / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D013450:Sulfones; D048051:p38 Mitogen-Activated Protein Kinases