Integrin alpha2beta1 regulates neutrophil recruitment and inflammatory activity in experimental colitis in mice.
BACKGROUND
Human inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), is associated with leukocyte accumulation in the inflamed intestinal tissue. Recent studies strongly suggest a role of beta1 integrin receptors in regulating tissue damage and disease symptoms related to inflammatory bowel disease. The aim of this study was to investigate the role of the collagen-binding alpha2beta1 integrin (CD49b/CD29) in dextran sodium sulfate-induced colitis in mice.


METHODS
Colitis was induced in mice through oral administration of 2% dextran sodium sulfate in drinking water. Rectal administration of anti-alpha2-monoclonal antibody (mAb) in 1 group was compared with oral treatment with betamethasone in another group and rectal administration of a control antibody in a third group. Clinical and histological signs of colitis, neutrophil infiltration into the colon mucosa, and gene expression of metalloproteinases were assessed.


RESULTS
Rectal administration of anti-alpha2-mAb was found to significantly reduce weight loss from 13.5% +/- 6.5% to 2.2% +/- 0.2% (P = 0.013 versus control mAb) and mucosal neutrophil infiltration from 47.2 +/- 10.0 to 6.6 +/- 8.0 neutrophils per counted area (P < 0.05 versus control mAb). Metalloproteinase gene expression was suppressed through anti-alpha2-mAb treatment. The protective effect against colitis seen after anti-alpha2beta1 integrin treatment was found to be favorable to the effect seen after high-dose oral betamethasone.


CONCLUSIONS
We demonstrate an alleviating action of the collagen-binding alpha2beta1 integrin in experimental colitis in mice and suggest that this effect is mediated by inhibition of neutrophil migration and activation. Local administration of function-blocking antibodies against integrin alpha2beta1 may provide novel avenues to treat inflammatory bowel disease.
Lundberg
Sofie
S
Department of Medicine, Unit of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm. Sofie.Lundberg@ki.se
Lindholm
Johan
J
Lindbom
Lennart
L
Hellström
Per M
PM
Werr
Joachim
J
D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000187:drug effects; D001623:Betamethasone / Q000494:pharmacology*; D001707:Biopsy, Needle; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000502:physiology; D011336:Probability; D011897:Random Allocation; D012307:Risk Factors; D012680:Sensitivity and Specificity; D015431:Weight Loss / Q000187:drug effects
D000911:Antibodies, Monoclonal; D038982:Integrin alpha2beta1; D001623:Betamethasone