title: Aryl hydrocarbon receptor contributes to the MEK/ERK-dependent maintenance of the immature state of human dendritic cells.
abstract: Dendritic cells (DCs) promote tolerance or immunity depending on their maturation state, which is enhanced or accelerated upon MEK-ERK signaling pathway inhibition. We have determined the contribution of MEK-ERK activation to the profile of gene expression of human immature monocyte-derived dendritic cells (MDDCs) and peripheral blood myeloid DCs. ERK inhibition altered the expression of genes that mediate Chemokine (C-C motif) ligand 19 (CCL19)-directed migration (CCR7) and low-density lipoprotein (LDL) binding (CD36, SCARB1, OLR1, CXCL16) by immature DCs. In addition, ERK upregulated CCL2 expression while impairing the expression of DC maturation markers (RUNX3, ITGB7, IDO1). MEK-ERK-regulated genes exhibited an overrepresentation of cognate sequences for the aryl hydrocarbon receptor (AhR) transcription factor, whose transcriptional and DNA-binding activities increased in MDDCs upon exposure to the MEK1/2 inhibitor U0126. Therefore, the MEK-ERK signaling pathway regulates antigen capture, lymph node homing, and acquisition of maturation-associated genes, and its contribution to the maintenance of the immature state of MDDCs and myeloid DCs is partly dependent on the activity of AhR. Since pharmacologic modulation of the MEK-ERK signaling pathway has been proposed as a potential therapeutic strategy for cancer, our findings indicate that ERK inhibitors might influence antitumor responses through regulation of critical DC effector functions.
authors: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors: Noemí
authors: N
authors: Aguilera-Montilla
authors: Sonia
authors: S
authors: Chamorro
authors: Concha
authors: C
authors: Nieto
authors: Fátima
authors: F
authors: Sánchez-Cabo
authors: Ana
authors: A
authors: Dopazo
authors: Pedro Maria
authors: PM
authors: Fernández-Salguero
authors: Jose Luis
authors: JL
authors: Rodríguez-Fernández
authors: Oscar M
authors: OM
authors: Pello
authors: Vicente
authors: V
authors: Andrés
authors: Ana
authors: A
authors: Cuenda
authors: Bárbara
authors: B
authors: Alonso
authors: Angeles
authors: A
authors: Domínguez-Soto
authors: Silvia
authors: S
authors: Sánchez-Ramón
authors: Angel L
authors: AL
authors: Corbí
mesh_terms: D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism
chemical_list: D002070:Butadienes; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D050677:Core Binding Factor Alpha 3 Subunit; D004791:Enzyme Inhibitors; D005419:Flavonoids; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D009570:Nitriles; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D054400:Receptors, CCR7; C493729:Runx3 protein, human; C113580:U 0126; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one