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Inorganic Arsenic Activates Reduced NADPH Oxidase in Human Primary Macrophages through a Rho Kinase/p38 Kinase Pathway¹

Anthony Lemarie^*, Emilie Bourdonnay^*, Claudie Morzadec^*, Olivier Fardel^*, and Laurent Vernhet^2,*

^* Institut National de la Santé et de la Recherche Médicale, Unité 620, Détoxication et Réparation Tissulaire, Université de Rennes 1 and Département Hématologie, Immunologie et Thérapie cellulaire, Centre Hospitalier Universitaire Pontchaillou, Rennes, France

Inorganic arsenic is an immunotoxic environmental contaminant to which millions of humans are chronically exposed. We recently demonstrated that human primary macrophages constituted a critical target for arsenic trioxide (As₂O₃), an inorganic trivalent form. To specify the effects of arsenic on macrophage phenotype, we investigated in the present study whether As₂O₃ could regulate the activity of NADPH oxidase, a major superoxide-generating enzymatic system in human phagocytes. Our results show that superoxide levels were significantly increased in a time-dependent manner in blood monocyte-derived macrophages treated with 1 µM As₂O₃ for 72 h. Concomitantly, As₂O₃ induced phosphorylation and membrane translocation of the NADPH oxidase subunit p47^phox and it also increased translocation of Rac1 and p67^phox. Apocynin, a selective inhibitor of NADPH oxidases, prevented both p47^phox translocation and superoxide production. NADPH oxidase activation was preceded by phosphorylation of p38-kinase in As₂O₃-treated macrophages. The p38-kinase inhibitor SB-203580 prevented phosphorylation and translocation of p47^phox and subsequent superoxide production. Pretreatment of macrophages with the Rho-kinase inhibitor Y-27632 was found to mimic inhibitory effects of SB-203580 and to prevent As₂O₃-induced phosphorylation of p38 kinase. Treatment with As₂O₃ also resulted in an increased secretion of the proinflammatory chemokine CCL18 that was fully inhibited by both apocynin and SB-203580. Taken together, our results demonstrate that As₂O₃ induced a marked activation of NADPH oxidase in human macrophages, likely through stimulation of a Rho-kinase/p38-kinase pathway, and which may contribute to some of the deleterious effects of inorganic arsenic on macrophage phenotype.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Association pour la Recherche sur le cancer and Ligue Contre le Cancer (Comité d’Ille-et-Vilaine). A.L. and E.B. are recipients of a fellowship from Ligue Nationale Contre le Cancer and Ligue Contre le Cancer (Comité d’Ille-et-Vilaine), respectively.

² Address correspondence and reprint requests to Dr. Laurent Vernhet, Institut National de la Santé et de la Recherche Médicale, Unité 620, Détoxication et Réparation Tissulaire, Université de Rennes 1, 2 avenue du Pr. Léon Bernard, 35043 Rennes, France. E-mail address: Laurent.Vernhet{at}rennes.inserm.fr

³ Abbreviations used in this paper: iAs, inorganic arsenic; ROCK, Rho kinase; ROS, reactive oxygen species; SOD, superoxide dismutase; DAPI, 4',6'-diamidino-2-phenylindole.

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