AhR- and c-maf-dependent induction of beta7-integrin expression in human macrophages in response to environmental polycyclic aromatic hydrocarbons.
In order to identify molecular targets of environmental polycyclic aromatic hydrocarbons (PAHs), we have analysed regulation of integrin (ITG) expression in PAH-exposed human macrophages. Among ITG subunits, beta7 ITG was found to be markedly up-regulated at both mRNA and protein levels in response to the prototypical PAH benzo(a)pyrene (BP). Knock-down of the transcription factor c-maf, known to control beta7 ITG expression, markedly impaired BP-mediated beta7 ITG induction. Moreover, chromatin immunoprecipitation and electrophoretic mobility shift assays showed BP-triggered binding of c-maf to a specific maf-responsive element found in beta7 ITG promoter. Such a binding, and also beta7 ITG induction, were however abolished in response to chemical inhibition of the aryl hydrocarbon receptor (AhR), to which PAHs bind. Taken together, these data establish beta7 ITG as a new molecular target of PAHs, whose up-regulation by these environmental contaminants most likely requires activation of co-operative pathways involving both AhR and c-maf.
Monteiro
Patricia
P
UMR-INSERM U620, Equipe Toxicity of Polycyclic Aromatic Hydrocarbons, IFR140, Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 2 Avenue du Professeur Léon Bernard, Rennes Cedex, France.
Gilot
David
D
Le Ferrec
Eric
E
Lecureur
Valérie
V
N'diaye
Monique
M
Le Vee
Marc
M
Podechard
Normand
N
Pouponnot
Celio
C
Fardel
Olivier
O
D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene / Q000008:administration & dosage; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D011084:Polycyclic Aromatic Hydrocarbons / Q000008:administration & dosage*; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D001564:Benzo(a)pyrene; D004785:Environmental Pollutants; D039641:Integrin beta Chains; D011084:Polycyclic Aromatic Hydrocarbons; D051257:Proto-Oncogene Proteins c-maf; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C495607:MAF protein, human; C091368:integrin beta7