Osteopontin attenuation of dextran sulfate sodium-induced colitis in mice.
Osteopontin (OPN) is a matricellular cytokine present in most tissues and body fluids; it is known to modulate immune responses. In previous studies using the dextran sulfate sodium (DSS) acute colitis model, we found exacerbated tissue destruction and reduced repair in OPN-null ((-/-)) mice compared with wild-type (WT) controls. As OPN is normally present in milk, we hypothesized that administration of OPN may protect the intestines from the adverse effects of experimental colitis. A volume of 20 or 2 microg/ml bovine milk OPN, dissolved in drinking water, was given to mice 24 h before, and during administration of DSS. Clinical parameters of colitis and neutrophil functions were analyzed as previously reported. Orally administered OPN was absorbed and detected in the colon mucosa by immunohistochemistry. The 20 microg/ml OPN- and DSS-treated WT mice showed 37% less weight loss and reduced colon shortening and spleen enlargements than control mice (P<0.05). OPN administration also reduced the disease activity index, improved red blood cell counts, and reduced gut neutrophil activity compared with the DSS-treated WT mice that were not administered OPN (P<0.05). Immunohistochemical detection of F4/80-labelled cells (macrophages) was also less frequent. The level of transforming growth factor beta1 (TGF-beta1) was increased and the levels of pro-inflammatory mediators decreased in colon tissue samples of OPN-treated mice analyzed by ELISA. The reversal of experimental colitis parameters by exogenous OPN was not as robust in the OPN(-/-) mice. Administration of prokaryotic-expressed recombinant OPN and bovine serum albumin were ineffective. This study shows that administration of a physiological concentration of milk OPN in drinking water ameliorates the destructive host response in DSS-induced acute colitis.
da Silva
Andre Paes Batista
AP
CIHR Group in Matrix Dynamics, University of Toronto, Toronto, ON, Canada.
Ellen
Richard P
RP
Sørensen
Esben S
ES
Goldberg
Harvey A
HA
Zohar
Ron
R
Sodek
Jaro
J
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D003106:Colon / Q000276:immunology / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008892:Milk / Q000737:chemistry*; D009504:Neutrophils / Q000187:drug effects; D053495:Osteopontin / Q000032:analysis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D012710:Serum Albumin, Bovine / Q000627:therapeutic use; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D018836:Inflammation Mediators; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D053495:Osteopontin; D012710:Serum Albumin, Bovine; D016264:Dextran Sulfate