Exacerbated tissue destruction in DSS-induced acute colitis of OPN-null mice is associated with downregulation of TNF-alpha expression and non-programmed cell death.
Osteopontin (OPN), a pro-inflammatory mediator, is constitutively expressed in normal gut and is upregulated in inflammatory colitis. To determine the significance of OPN in inflammatory bowel disease, we studied the development of acute, experimental colitis induced by dextran sulfate sodium (DSS) in OPN-null and wild-type (WT) mice. OPN expression was markedly increased in WT diseased colons, while a higher disease activity index, including spleen enlargement, bowel shortening, and mucosal destruction, was observed in OPN-null mice. Although peripheral blood neutrophil numbers were lower in DSS-treated OPN-null mice, tissue myeloperoxidase levels, reflecting enhanced neutrophil activity, were increased in the diseased colons. In comparison, lymphocyte numbers in peripheral blood were increased earlier than in DSS-treated WT mice. Despite a significantly greater spleen enlargement, flow cytometric analysis of splenocytes from the DSS-treated OPN-null mice revealed lower numbers of differentiated macrophages and (CD4+ and CD8alpha+) lymphocytes. Whereas pro-inflammatory cytokines, including G-CSF, RANTES, MIP1alpha, and TNF-alpha, were increased < 10-fold in DSS-treated WT splenocytes, expression of these cytokines was dramatically suppressed in the DSS-treated OPN-null splenocytes as well as gut tissues. The suppressed TNF-alpha response in OPN-null mice was reflected in a marked increase in non-apoptotic cell death in diseased colons. Collectively, these studies demonstrate that OPN is required for mucosal protection in acute inflammatory colitis.
Da Silva
Andre Paes Batista
AP
CIHR Group in Matrix Dynamics, University of Toronto, Toronto, Ontario, Canada.
Pollett
Aaron
A
Rittling
Susan R
SR
Denhardt
David T
DT
Sodek
Jaro
J
Zohar
Ron
R
D000818:Animals; D001835:Body Weight; D016923:Cell Death; D003092:Colitis / Q000235:genetics* / Q000473:pathology*; D003106:Colon / Q000473:pathology; D016264:Dextran Sulfate / Q000494:pharmacology*; D005786:Gene Expression Regulation; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin; D012795:Sialoglycoproteins / Q000172:deficiency* / Q000235:genetics; D013154:Spleen / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D053495:Osteopontin; D016264:Dextran Sulfate