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Heme Oxygenase-1 Is a Critical Regulator of Nitric Oxide Production in Enterohemorrhagic Escherichia coli-Infected Human Enterocytes¹

Marjolaine Vareille^*, François Rannou^2,, Natacha Thélier^2,, Anne-Lise Glasser, Thibaut de Sablet^*, Christine Martin^* and Alain P. Gobert^3,*

^* Institut National de la Recherche Agronomique, Unité de Microbiologie UR454, Saint-Genès-Champanelle; Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 747, Laboratoire de Pharmacologie, Toxicologie et Signalisation Moléculaire, Université Paris Descartes, Paris; and Pathogénie Bactérienne Intestinale, USC Institut National de la Recherche Agronomique 2018, Université d’Auvergne, Clermont-Ferrand, France

Enterohemorrhagic Escherichia coli (EHEC) are the causative agent of hemolytic-uremic syndrome. In the first stage of the infection, EHEC interact with human enterocytes to modulate the innate immune response. Inducible NO synthase (iNOS)-derived NO is a critical mediator of the inflammatory response of the infected intestinal mucosa. We therefore aimed to analyze the role of EHEC on iNOS induction in human epithelial cell lines. In this regard, we show that EHEC down-regulate IFN--induced iNOS mRNA expression and NO production in Hct-8, Caco-2, and T84 cells. This inhibitory effect occurs through the decrease of STAT-1 activation. In parallel, we demonstrate that EHEC stimulate the rapid inducible expression of the gene hmox-1 that encodes for the enzyme heme oxygenase-1 (HO-1). Knock-down of hmox-1 gene expression by small interfering RNA or the blockade of HO-1 activity by zinc protoporphyrin IX abrogated the EHEC-dependent inhibition of STAT-1 activation and iNOS mRNA expression in activated human enterocytes. These results highlight a new strategy elaborated by EHEC to control the host innate immune response.

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 Institut National de la Recherche Agronomique and Région Auvergne (to M.V.), from Université Paris Descartes, Arthritis Fondation Courtin, Institut National de la Santé et de la Recherche Médicale (to F.R.), and from Société Française de Rhumatologie (to N.T.).

² F.R. and N.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Alain P. Gobert, Unité de Microbiologie, Institut National de la Recherche Agronomique, Centre de Theix, 63122 Saint-Genès-Champanelle, France. E-mail address: agobert{at}clermont.inra.fr

⁴ Abbreviations used in this paper: EHEC, enterohemorrhagic Escherichia coli; LEE, locus of enterocyte effacement; iNOS, inducible NO synthase; Stx, Shiga-toxin; HO, heme oxygenase; Bay 11–7082, (E)3-[(4-methylphenyl)sulfonyl]-2-propenenitrile; ZnPP, zinc protoporphyrin IX; CO, carbon monoxide; CORM-2, tricarbonyldichlororuthenium-(II)-dimer; siRNA, small interfering RNA; EPEC, enteropathogenic E. coli.