Exacerbated tissue destruction in DSS‐induced acute colitis of OPN‐null mice is associated with downregulation of TNF‐α expression and non‐programmed cell death

Abstract

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.

Osteopontin attenuation of dextran sulfate sodium-induced colitis in mice

“…[13][14][15] We have shown that OPN is upregulated in epithelial cells of the intestinal mucosa during experimental colitis. 16 We have also shown that OPN is chemoattractive for neutrophils but not involved in phagocytosis or generation of reactive oxygen species. 17 Yet, OPN regulates macrophage functions such as migration, activation, and phagocytosis.…”

“…[21][22][23][24] Our previous study using the experimental acute colitis model found a greater susceptibility of OPN À/À mice than wild-type (WT) mice to DSS-induced colitis. 16 Clinical parameters of colitis, such as weight loss, disease activity scores, colon shortening, and spleen enlargement, were significantly greater in OPN À/À mice and accompanied by an exacerbation of intestinal tissue damage. Tissue destruction was associated with the persistence of neutrophils and reduced survival of enterocytes.…”

Dextran Sulfate Sodium‐induced Colitis Generates a Transient Thymic Involution – Impact on Thymocyte Subsets

“…This may indicate that the intrathymic maturation of the thymocytes escaping apoptosis is accelerated due to the increased need of peripheral T lymphocytes during inflammation. Interestingly, T lymphocytes have been shown to increase in blood during DSS-evoked colitis [29]. The immediate stress responses in an acute inflammation can be compared with the events seen in traumatized patients.…”

Osteopontin: Role in immune regulation and stress responses

“…Its expression is elevated in response to mechanical stress in bone and the vasculature Yoshitake et al, 1999;Denhardt and Noda, 1998). OPN levels are elevated in response to the oxidative stresses existing in tumors, after reperfusion injury, and in inflammatory diseases such as inflammatory bowel disease, chronic obstructive pulmonary disease, and Parkinson's disease (Maetzler et al, 2007;Da Silva et al, 2006;Heguy et al, 2007). Our finding that mice lacking OPN are protected from stress-induced lymphoid organ atrophy is intriguing because this implies that OPN also functions as a stress mediator.…”