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Originally published In Press as doi:10.1074/jbc.M303749200 on June 17, 2003

J. Biol. Chem., Vol. 278, Issue 36, 33878-33886, September 5, 2003
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The Invasive Phenotype of Shigella flexneri Directs a Distinct Gene Expression Pattern in the Human Intestinal Epithelial Cell Line Caco-2*,

Thierry Pédron {ddagger}, Christelle Thibault § and Philippe J. Sansonetti {ddagger} ¶

From the {ddagger}Unité de Pathogénie Microbienne Moleculaire et Unité INSERM 389, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris Cedex 15 and the §Institut de Génétique et de Biologie Moléculaire et Cellulaire,1 Rue Laurent Fries, 67404 ILLKIRCH Cedex, Strasbourg, France

Invasion of the human colonic epithelium by Shigella flexneri causes inflammation that disrupts the intestinal barrier. Invaded intestinal epithelial cells are the major source of mediators recruiting the inflammatory infiltrate. To better characterize the global response of intestinal epithelial cells to Shigella invasion, Caco-2 cells were infected by an invasive isolate of S. flexneri 5a, and their transcriptome was analyzed by Affymetrix (Santa Clara, CA) microarrays (12,000 genes) and compared with these elicited by a non-invasive Shigella mutant and tumor necrosis factor (TNF)-{alpha}. The invasive and non-invasive strains enhanced transcription of a common pattern of 240 genes, among which genes encoding isoforms of cytochrome P-450 were induced. These genes were not induced by TNF-{alpha}. Conversely, both the invasive strain and TNF-{alpha} induced a common set of 18 genes, mainly encoding proinflammatory molecules. They also induced specific sets of genes. The transcriptome induced by the invasive strain was characterized by the induction of early genes (i.e. expressed within the first 45 min of invasion) and late genes (i.e. after 60 min of invasion) whose pattern was strongly biased toward stimulation of granulopoiesis, chemoattraction, activation, and adherence of polymorphonuclear leukocytes. When compared with a non-invasive Shigella and TNF-{alpha}, invasive Shigella induced a narrow transcriptome that seems to program infected epithelial cells to recruit a mucosal polymorphonuclear leukocyte to infiltrate. Dramatic increase in IL-8 gene transcription points to this chemokine as the major molecule orchestrating mucosal inflammation in shigellosis.


Received for publication, April 10, 2003 , and in revised form, June 12, 2003.

* This work was supported by a Program from the French Ministry of Research and Advanced Technologies and by a special APEX fund from INSERM. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplementary data showing complete list of genes whose transcription was up-regulated.

To whom correspondence shoule be addressed. Tel.: 33-1-40-61-30-95; Fax: 33-1-45-68-89-53; E-mail: psanson{at}pasteur.fr.


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