AhR- and c-maf-dependent induction of β7-integrin expression in human macrophages in response to environmental polycyclic aromatic hydrocarbons

https://doi.org/10.1016/j.bbrc.2007.04.111Get rights and content

Abstract

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, β7 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 β7 ITG expression, markedly impaired BP-mediated β7 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 β7 ITG promoter. Such a binding, and also β7 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 β7 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.

Section snippets

Experimental procedures

Chemicals and reagents. PAHs and α-naphthoflavone (αNF) were purchased from Sigma–Aldrich (St. Louis, MO). TCDD was obtained from Cambridge Isotope Laboratories (Cambridge, MA). Rabbit polyclonal Ab anti-AhR (SA-210) was obtained from Biomol Research Labs (Plymouth, PA) whereas rabbit non-specific IgG was from Amersham Biosciences (Orsay, France). Rabbit polyclonal Abs anti-c-maf (M-153) and anti-p38 MAPK and mouse monoclonal Ab anti-lamin A/C were purchased from Santa Cruz Biotechnology (Tebu,

PAH-triggered induction of β7 ITG expression

ITG family comprises eighteen α and eight β subunits which assemble to form at least 24 heterodimers (Fig. 1A), and whose mRNA levels in human primary macrophages exposed to 10 μM BP were first investigated by RT-qPCR (Fig. 1B). α11, αL, αE, β7, and β8 ITG mRNA levels were found to be significantly increased by the PAH whereas, by contrast, level of α9 ITG was decreased when compared to untreated macrophages (Fig. 1B). Other ITG subunits, constitutively expressed in untreated primary

Discussion

In the present report, we demonstrate that β7 ITG constitutes a robust molecular target of PAHs. Indeed, these environmental contaminants were shown to in vitro up-regulate β7 ITG in human macrophages at both mRNA and protein levels whereas in vivo PAH exposure enhanced β7 ITG expression in rat intestine. Such an up-regulation of β7 ITG by PAHs likely accounts for the induction of this ITG in response to diesel particles since such particles are well-known to contain PAHs [8].

AhR, well-known to

Acknowledgments

This work was supported by grants from Agence Française de Sécurité Sanitaire de l’Environnement et du Travail (AFSSET). Patricia Monteiro is a recipient of fellowship from the Ligue contre le Cancer. We thank Drs. D. Lagadic-Gossmann, A. Eychène, and M.P. Felder-Schmittbuhl for helpful discussions. We are grateful to Dr. L. Sparfel for in vivo experiments.

References (26)

Cited by (30)

  • Gene expression profiles of putative biomarkers in juvenile loggerhead sea turtles (Caretta caretta) exposed to polycyclic aromatic hydrocarbons

    2019, Environmental Pollution
    Citation Excerpt :

    TLN1 plays a pivotal role in activating integrin pathways that in turn regulate cell adhesion, proliferation and survival (Calderwood, 2004). It is noteworthy that integrins have been identified as a new major molecular target of PAH exposure in macrophages (Monteiro et al., 2007). It is therefore tempting to speculate that PAHs enhance expression of Talin1 in loggerhead whole blood cells and, by this way, may alter physiological processes related to integrin-related signaling activities.

  • Aryl hydrocarbon receptor activation by benzo(a)pyrene inhibits proliferation of myeloid precursor cells and alters the differentiation state as well as the functional phenotype of murine bone marrow-derived macrophages

    2018, Toxicology Letters
    Citation Excerpt :

    Takahashi and colleagues demonstrated that binding of the transcription factors MafB and c-Maf on the half-site of Maf recognition elements in the promoter region of F4/80 is essential for expression (Moriguchi et al., 2006; Nakamura et al., 2009). Further, it was shown in human macrophages that especially c-Maf may interact with ligand-activated AhR (Monteiro et al., 2007), what may explain an AhR-dependent regulation of F4/80. Since F4/80 is required for the induction of antigen-specific regulatory T cells (Lin et al., 2005), the regulation of F4/80 caused by AhR activation may influence the number of regulatory T cells in vivo.

  • The Aryl Hydrocarbon Receptor and Immunity

    2018, Comprehensive Toxicology: Third Edition
View all citing articles on Scopus
View full text