Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification.
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.
Campbell
Eric L
EL
Mucosal Inflammation Program, Department of Medicine, University of Colorado, Aurora, CO 80045, USA.
MacManus
Christopher F
CF
Kominsky
Douglas J
DJ
Keely
Simon
S
Glover
Louise E
LE
Bowers
Brittelle E
BE
Scully
Melanie
M
Bruyninckx
Walter J
WJ
Colgan
Sean P
SP
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
D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D015118:Eicosapentaenoic Acid; D000469:Alkaline Phosphatase; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid