title: The p38-MSK1 signaling cascade influences cytokine production through CREB and C/EBP factors in human neutrophils.
abstract: Neutrophils influence innate and adaptative immunity by generating numerous cytokines and chemokines whose regulation largely depends on transcriptional activators such as NF-κB and C/EBP factors. In this study, we describe the critical involvement of CREB transcription factors (CREB1 and activating transcription factor-1) in this functional response as well as relevant upstream signaling components. Neutrophil stimulation with LPS or TNF led to the phosphorylation, DNA binding activity, and chemokine promoter association of CREB1 and activating transcription factor-1. These responses occurred downstream of the p38-MSK1 signaling axis, as did the phosphorylation and promoter association of another bZIP factor, C/EBPβ. Conversely, inhibition of RSK1 failed to alter the phosphorylation of either CREB1 or C/EBPβ in neutrophils. From a more functional standpoint, the inhibition of p38 MAPK or MSK1 interfered with cytokine generation in neutrophils. Likewise, overexpression of a dominant-negative CREB1 mutant (K-CREB) or of a point mutant (S133A) resulted in a decreased ability of human neutrophil-like PLB-985 cells to generate inflammatory cytokines (CXCL8, CCL3, CCL4, and TNF-α). Collectively, our data show the involvement of CREB1 in neutrophil cytokine production, the key role of its S133 residue, important upstream signaling events, and the parallel activation of another bZIP factor. These are all potential molecular targets that could be exploited in the context of several chronic inflammatory diseases that prominently feature neutrophils and their products.
authors.affiliation: Service de Pneumologie, Faculté de Médecine, Université de Sherbrooke, Sherbrooke, Québec J1H 5N4, Canada;
authors.forename: Thomas Z
authors.initials: TZ
authors.lastname: Mayer
authors.forename: François A
authors.initials: FA
authors.lastname: Simard
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cloutier
authors.forename: Harsh
authors.initials: H
authors.lastname: Vardhan
authors.forename: Claire M
authors.initials: CM
authors.lastname: Dubois
authors.forename: Patrick P
authors.initials: PP
authors.lastname: McDonald
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D008070:Lipopolysaccharides; D020935:MAP Kinase Signaling System; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D048069:Tumor Necrosis Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051697:Activating Transcription Factor 1; D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D008070:Lipopolysaccharides; D048069:Tumor Necrosis Factors; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D048051:p38 Mitogen-Activated Protein Kinases