Effects of mouse and human lipocalin homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin on gastrointestinal mucosal integrity and repair.
OBJECTIVE
The lipocalin superfamily, including the mouse and human homologues 24p3/lcn2 and neutrophil gelatinase-associated lipocalin, show great functional diversity including roles in olfaction, transportation, and prostaglandin synthesis in mammals. Their potential role in maintaining gastrointestinal mucosal integrity and repair is, however, unclear.


METHODS
Changes in 24p3/lcn2 expression in the mouse gut in response to various noxious agents were examined using Northern blot, in situ hybridization, and immunohistochemistry. Effects of recombinant 24p3/lcn2 on proliferation ([3H]-thymidine uptake), and restitution (cell-wounding migration) were assessed using human colonic HT29 and HCT116 cells. In addition, the effects of recombinant 24p3/lcn2 on the amount of gastric damage were assessed in rats treated with indomethacin (20 mg/kg) and restraint.


RESULTS
Marked up-regulation of expression of 24p3/lcn2 was seen throughout the gut in response to indomethacin or dextran sodium sulfate treatment. Expression was increased particularly in the surface epithelial cells and infiltrating inflammatory cells. Proliferation and restitution assays in the presence of recombinant wild-type sequence neutrophil gelatinase-associated lipocalin, wild-type cys(98)-24p3/lcn2, and mutant ala98-24p3/lcn2 showed that all 3 peptides caused a 3- to 4-fold increase in promigratory activity (P < .01 vs control) but did not influence proliferation. The administration of wild-type cys98-, or mutant ala98-24p3/lcn2 (25 and 50 microg/kg/h, respectively), given via the subcutaneous route, both caused similar reductions in the rat gastric damage model (60% reduction at highest dose, P < .01 vs control), although oral administration was ineffective.


CONCLUSIONS
24p3/lcn2 facilitates mucosal regeneration by promoting cell migration.
Playford
Raymond J
RJ
Centre for Gastroenterology, Barts and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom. r.playford@qmul.ac.uk
Belo
Angelica
A
Poulsom
Richard
R
Fitzgerald
Anthony J
AJ
Harris
Kevin
K
Pawluczyk
Isabella
I
Ryon
Joel
J
Darby
Thameen
T
Nilsen-Hamilton
Marit
M
Ghosh
Subrata
S
Marchbank
Tania
T
D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000166:cytology* / Q000187:drug effects; D000071068:Lipocalin-2; D054834:Lipocalins; D051379:Mice; D008810:Mice, Inbred C57BL; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D012313:RNA / Q000235:genetics; D011994:Recombinant Proteins; D015854:Up-Regulation
D000209:Acute-Phase Proteins; D002352:Carrier Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C071332:Lcn2 protein, mouse; D012313:RNA