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Infect. Immun. doi:10.1128/IAI.00645-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Prostaglandin E₂ produced by Entamoeba histolytica binds to EP4 receptors and stimulate IL-8 production in human colonic cells

Department of Microbiology and Infectious Diseases, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1

^* To whom correspondence should be addressed. Email: kchadee{at}ucalgary.ca.

	Abstract

The pathogenesis of Entamoeba histolytica in the colon occurs in a step-wise fashion beginning with colonization to the mucin layer followed by stimulation of a pro-inflammatory response that cause non-specific tissue damage that may facilitate parasite invasion to the underlying colonic mucosa. Unfortunately, the parasite and/or host factors that stimulate a pro-inflammatory response in the gut are poorly understood. In this study, we show that live E. histolytica or secretory (SP) and soluble ameba components (SAP) can markedly increase interleukin-8 (IL-8) mRNA expression and protein production in colonic epithelial cells. The IL-8 stimulatory molecule produced by live ameba was identified as PGE₂ as trophozoites treated with cyclooxygenase inhibitors inhibited the biosynthesis of PGE₂ and abrogated IL-8 production induced by live parasites or ameba components. Moreover, using specific prostaglandin EP2 and EP4 receptor agonists and antagonists we have identified that PGE₂ binds exclusively through EP4 receptors in colonic epithelial cells to stimulate IL-8. Silencing of EP4 receptors with EP4 siRNA completely abrogated SP- and SAP-induced IL-8 production. These studies have identified bioactive PGE₂ as a one of the major virulent factor produced by E. histolytica that can stimulate the potent neutrophil chemokine and activator IL-8, which can trigger an acute host inflammatory response. Thus, the induction of IL-8 in response to E. histolytica-derived PGE₂ may provide a mechanism to explain the initiation and amplification of acute inflammation associated with intestinal amebiasis.