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J. Biol. Chem., Vol. 281, Issue 36, 26112-26120, September 8, 2006

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Suppression of NF-B Activation by Entamoeba histolytica in Intestinal Epithelial Cells Is Mediated by Heat Shock Protein 27^*

From the Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Little is known about the pathogenesis of Entamoeba histolytica and how epithelial cells respond to the parasite. Herein, we characterized the interactions between E. histolytica and colonic epithelial cells and the role macrophages play in modulating epithelial cell responses. The human colonic epithelial cell lines Caco-2 and T84 were grown either as monoculture or co-cultured in transwell plates with differentiated human THP-1 macrophages for 24 h before stimulation with soluble amebic proteins (SAP). In naive epithelial cells, prolonged stimulation with SAP reduced the levels of heat shock protein (Hsp) 27 and 72. However in THP-1 conditioned intestinal epithelial cells SAP enhanced Hsp27 and Hsp72, which was dependent on the activation of ERK MAP kinase. Hsp synthesis induced by SAP conferred protection against oxidative and apoptotic injuries. Treatment with SAP inhibited NF-B activation induced by interleukin-1; specifically, the NF-B-DNA binding, nuclear translocation of p65 subunit, and phosphorylation of IB- were reduced. Gene silencing by small interfering RNA confirmed the role of Hsp27 in suppressing NF-B activation at IB kinase (IKK) level. By co-immunoprecipitation studies, we found that Hsp27 interacts with IKK- and IKK-, and this association was increased in SAP-treated conditioned epithelial cells. Overexpression of wild type Hsp27 amplified the effects of SAP, whereas a phosphorylation-deficient mutant of Hsp27 abrogated SAP-induced NF-B inhibition. In conditioned epithelial cells, Hsp27 was phosphorylated at serine 15 after prolonged exposure to SAP. This mechanism may explain the absence of colonic inflammation seen in the majority of individuals infected with E. histolytica.

Received for publication, March 2, 2006 , and in revised form, July 12, 2006.

^* This work was supported by grants from the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. 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 Recipient of a McGill University Graduate Fellowship.

² To whom correspondence should be addressed: University of Calgary, Faculty of Medicine, Dept. of Microbiology & Infectious Diseases, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada. Tel.: 403-210-3975; Fax: 403-270-2772; E-mail: kchadee{at}ucalgary.ca.

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