title: Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification.
abstract: Resolvin-E1 (RvE1) has been demonstrated to promote inflammatory resolution in numerous disease models. Given the importance of epithelial cells to coordination of mucosal inflammation, we hypothesized that RvE1 elicits an epithelial resolution signature. Initial studies revealed that the RvE1-receptor (ChemR23) is expressed on intestinal epithelial cells (IECs) and that microarray profiling of cells exposed to RvE1 revealed regulation of inflammatory response gene expression. Notably, RvE1 induced intestinal alkaline phosphatase (ALPI) expression and significantly enhanced epithelial ALPI enzyme activity. One role recently attributed to ALPI is the detoxification of bacterial LPS. In our studies, RvE1-exposed epithelia detoxified LPS (assessed by attenuation of NF-kappaB signaling). Furthermore, in epithelial-bacterial interaction assays, we determined that ALPI retarded the growth of Escherichia coli. To define these features in vivo, we used a murine dextran sulfate sodium (DSS) model of colitis. Compared with vehicle controls, administration of RvE1 resulted in significant improvement of disease activity indices (e.g., body weight, colon length) concomitant with increased ALPI expression in the intestinal epithelium. Moreover, inhibition of ALPI activity resulted in increased severity of colitis in DSS-treated animals and partially abrogated the protective influence of RvE1. Together, these data implicate a previously unappreciated role for ALPI in RvE1-mediated inflammatory resolution.
authors.affiliation: Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Campbell
authors.forename: Christopher F
authors.initials: CF
authors.lastname: MacManus
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Simon
authors.initials: S
authors.lastname: Keely
authors.forename: Louise E
authors.initials: LE
authors.lastname: Glover
authors.forename: Brittelle E
authors.initials: BE
authors.lastname: Bowers
authors.forename: Melanie
authors.initials: M
authors.lastname: Scully
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Bruyninckx
authors.forename: Sean P
authors.initials: SP
authors.lastname: Colgan
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics*; D000818:Animals; D003092:Colitis / Q000517:prevention & control; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004847:Epithelial Cells / Q000737:chemistry; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000201:enzymology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D011956:Receptors, Cell Surface / Q000032:analysis; D015533:Transcriptional Activation
chemical_list: D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D015118:Eicosapentaenoic Acid; D000469:Alkaline Phosphatase; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid