Intestinal alkaline phosphatase contributes to the reduction of severe intestinal epithelial damage.
Inflammatory bowel disease is characterized by chronic inflammation of the intestine and is accompanied by damage of the epithelial lining and by undesired immune responses towards enteric bacteria. It has been demonstrated that intestinal alkaline phosphatase (iAP) protects against the induction of inflammation, possibly due to dephosphorylation of lipopolysaccharide (LPS). The present study investigated the therapeutic potential of iAP in intestinal inflammation and epithelial damage. Intestinal epithelial damage was induced in C57BL/6 mice using detran sulfate sodium (DSS) and iAP was administered 4days after initial DSS exposure. Loss in body weight was significantly less in iAP-treated mice and accompanied with reduced colon damage (determined by combination of crypt loss, loss of goblet cells, oedema and infiltrations of neutrophils). Treatment with iAP was more effective in case of severe inflammation compared to situations of mild to moderate inflammation. Rectal administration of LPS into a moderate inflamed colon did not aggravate inflammation. Furthermore, soluble iAP did not lower LPS-induced nuclear factor-kappaB activation in epithelial cells in vitro but induction of cellular AP expression by butyrate resulted in decreased LPS response. In conclusion, the present study shows that oral iAP administration has beneficial effects in situations of severe intestinal epithelial damage, whereas in moderate inflammation endogenous iAP may be sufficient to counteract disease-aggravating effects of LPS. An approach including iAP treatment holds a therapeutic promise in case of severe inflammatory bowel disease.
Institute for Risk Assessment Sciences, Department of Immunotoxicology Utrecht University, Utrecht, The Netherlands. m.bol-schoenmakers@uu.nl
Marianne
M
Bol-Schoenmakers
Daniëlle
D
Fiechter
Willem
W
Raaben
Ine
I
Hassing
Rob
R
Bleumink
Daniëlle
D
Kruijswijk
Kelly
K
Maijoor
Monique
M
Tersteeg-Zijderveld
Ruud
R
Brands
Raymond
R
Pieters
D000469:Alkaline Phosphatase / Q000627:therapeutic use*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism
D002087:Butyrates; D018925:Chemokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016264:Dextran Sulfate; D009195:Peroxidase; D000469:Alkaline Phosphatase