Role of Osteopontin During Dextran Sulfate Sodium-induced Colitis.

摘要

Osteopontin (OPN) is a matricellular cytokine found in most tissues and body fluids. It is involved in a variety of cell processes by binding to integrins and CD44 receptors, and it modulates immune responses. To investigate the functions of OPN during colitis the DSS acute colitis model in OPN-/- and WT control mice was utilized. OPN-/- mice were more susceptible to DSS-induced colitis than the DSS-treated WT control mice. The increased susceptibility of the OPN-/- mice was characterized by greater intestinal crypt destruction; high myeloperoxidase activity of infiltrating neutrophils; lack of differentiation of inflammatory cells such as lymphocytes subsets (CD4+, CD8+) and macrophages (F4/80); reduced production of certain cytokines, especially TNF-alpha; and non-programmed cell death of enterocytes. It is postulated that the hyperactivity of neutrophils may explain the increased tissue destruction during experimental colitis in the absence of OPN. Analysis of OPN's impact on neutrophil function showed that while OPN may be important for the recruitment and migration of neutrophils, the expression of OPN by neutrophils is not required for manifestation of their destructive capabilities. This would suggest that OPN administration may protect the intestines from the adverse effects of colitis. Exogenous bovine milk OPN (20 mug/ml), administered for 8 days dissolved in the drinking water, ameliorated DSS-induced colitis. It diminished signs of disease, with a greater impact in the WT than the OPN-/- mice. It reduced the levels of neutrophils, macrophages, and pro-inflammatory mediators in the colon tissue. Recombinant OPN failed to reproduce the beneficial effects of milk OPN, which suggests that post-translational modifications of OPN are crucial to ameliorate experimental colitis. Collectively, these studies demonstrate that OPN has a protective effect during experimental colitis and that the oral administration of bovine milk OPN (20 mug/ml) ameliorates acute DSS-induced colitis. The results of this study also imply that the protective effect probably depends on a post-translationally modified form of OPN, and may require intracellular-OPN as a cofactor for significant attenuation of colitis. Future research could concentrate on more detailed investigation of these latter findings to determine OPN's mechanism of action.