Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification.

Abstract

Inflammatory bowel diseases are disorders of unknown etiology characterized by inappropriate inflammation. There is recent intense interest in understanding mechanisms of inflammatory resolution. Resolvin‐E1 (RvE1) has been demonstrated to promote resolution in numerous disease models. Given the importance of epithelial cells in coordinating mucosal inflammation, we hypothesized that RvE1 elicits an epithelial inflammatory resolution signature. Microarray profiling of epithelial cells exposed to RvE1, revealed transcriptional induction of numerous inflammatory response genes. Notably, RvE1 induced intestinal alkaline phosphatase (ALPI) expression and enhanced epithelial ALPI enzymatic activity. ALPI was recently demonstrated to detoxify bacterial LPS. In our studies, both purified ALPI and "conditioned" LPS‐containing media derived from RvE1‐exposed epithelia were demonstrated to detoxify LPS. To define these features in vivo, we employed a murine DSS model of colitis. Compared to vehicle controls, administration of RvE1 resulted in significant improvement of disease activity indices. RvE1 treatment resulted in significantly increased ALPI expression in murine intestinal epithelial cells. Moreover, disease severity inversely correlated with ALPI expression. Taken together, these data implicate a previously unappreciated role for ALPI in RvE1 mediated inflammatory resolution.

Impaired Mucosal Barrier Function in the Small Intestine of the Cystic Fibrosis Mouse

“…Previous work showed that oral L-Phe inhibited IAP activity and increased the severity of experimental colitis (39). In mice treated with L-Phe there was not a significant change in permeability in either WT or CF mice (Fig.6).…”

“…To address this we used the IAP inhibitor L-Phe, added to the liquid diet. Previous work showed that oral L-Phe increased passage of gavaged LPS into blood in rats (56) and increased the severity of experimental colitis induced with dextran sodium sulfate in mice (39). When we treated mice with oral LPhe, intestinal permeability was not affected in either WT or CF mice.…”

“…Some mice received purified calf intestinal alkaline phosphatase (Lee Biosolutions, St. Louis MO USA) (35-38), at 13.3 U/ml in the liquid diet. Another group of mice received the AP selective inhibitor L-phenylalanine (L-Phe) (39), at 10 mM in the liquid diet. Another group of mice was maintained on standard mouse chow and given an osmotic laxative (Colyte® formulation) in their drinking water (40).…”

Omega-3 polyunsaturated fatty acids for the treatment and prevention of colorectal cancer

“…Both 18 R and 18 S enantiomers of RvE1 are ligands for ChemR23 and BLT1 G protein-coupled receptors 29. RvE1 has been shown to induce expression of intestinal alkaline phosphatase in human CRC cells in a ChemR23-dependent manner and abrogate chemically induced colitis in mice 34. It is currently not known whether ω-3 PUFA-derived resolvins exhibit antineoplastic activity.…”

GROWTH AND DEVELOPMENT SYMPOSIUM: Endotoxin, inflammation, and intestinal function in livestock1,2

“…Another example indicating that AP is regulated by dietary lipids is that cod liver oil rich in n-3 fatty acid has been shown to increase the secretion of intestinal AP (Kaur et al, 2007). Interestingly, this may be explained by the increased expression resolvin-El, an antiinflammatory n-3 fatty acid lipid mediator, which induces AP activity (Campbell et al, 2010). Furthermore, increased dietary fat consumption reduces intestinal AP activity in obesity-prone rodents (de La Serre et al, 2010).…”