title: Prostaglandin E2 produced by Entamoeba histolytica signals via EP4 receptor and alters claudin-4 to increase ion permeability of tight junctions.
abstract: Entamoeba histolytica is a protozoan parasite that causes amebic dysentery characterized by severe watery diarrhea. Unfortunately, the parasitic factors involved in the pathogenesis of diarrhea are poorly defined. Prostaglandin E(2) (PGE(2)) is a host lipid mediator associated with diarrheal diseases. Intriguingly, E. histolytica produces and secretes this inflammatory molecule. We investigated the mechanism whereby ameba-derived PGE(2) induces the onset of diarrhea by altering ion permeability of paracellular tight junctions (TJs) in colonic epithelia. PGE(2) decreased barrier integrity of TJs in a dose- and time-dependent manner, as measured by transepithelial resistance. PGE(2) signals were selectively transduced via the EP4 receptor. Furthermore, PGE(2) signaling decreased TJ integrity, as revealed by EP receptor-specific agonist and antagonist studies. Loss of mucosal barrier integrity corresponded with increased ion permeability across TJs. Subcellular fractionation and confocal microscopy studies highlighted a significant spatial alteration of an important TJ protein, claudin-4, that corresponded with increased sodium ion permeability through TJs toward the lumen. Moreover, PGE(2)-induced luminal chloride secretion was a prerequisite for alterations at TJs. Thus, the gradient of NaCl created across epithelia could serve as a trigger for osmotic water flow that leads to diarrhea. Our results highlight a pathological role for E. histolytica-derived PGE(2) in the onset of diarrhea.
authors.affiliation: Department of Microbiology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Manigandan
authors.initials: M
authors.lastname: Lejeune
authors.forename: France
authors.initials: F
authors.lastname: Moreau
authors.forename: Kris
authors.initials: K
authors.lastname: Chadee
mesh_terms: D002460:Cell Line; D062506:Claudin-4; D057167:Claudins / Q000378:metabolism*; D003106:Colon / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004748:Entamoeba histolytica / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D007413:Intestinal Mucosa / Q000378:metabolism; D018613:Microscopy, Confocal / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D010539:Permeability; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism*; D012964:Sodium / Q000737:chemistry; D013347:Subcellular Fractions / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism
chemical_list: C568157:CLDN4 protein, human; D062506:Claudin-4; D057167:Claudins; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012964:Sodium; D015232:Dinoprostone