The role of PGE₂ in intestinal inflammation and tumorigenesis

Release of the free fatty acid arachidonic acid (AA) by cytoplasmic phospholipase A₂ (cPLA₂) and its subsequent metabolism by the cyclooxygenase and lipoxygenase enzymes produces a broad panel of eicosanoids including prostaglandins (PGs). This study sought to investigate the roles of these mediators in experimental models of inflammation and inflammation-associated intestinal tumorigenesis. Using the dextran sodium sulfate (DSS) model of experimental colitis, we first investigated how a global reduction in eicosanoid production would impact intestinal injury by utilizing cPLA₂ knockout mice. cPLA₂ deletion enhanced colonic injury, reflected by increased mucosal ulceration and pro-inflammatory cytokine expression. Increased disease severity was associated with a significant reduction in the levels of several eicosanoid metabolites, including PGE₂. We further assessed the precise role of PGE₂ synthesis on mucosal injury and repair by utilizing mice with a genetic deletion of microsomal PGE synthase-1 (mPGES-1), the terminal synthase in the formation of inducible PGE₂. DSS exposure caused more extensive acute injury as well as impaired recovery in knockout mice compared to wild-type littermates. Increased intestinal damage was associated with both reduced PGE₂ levels as well as altered levels of other eicosanoids including PGD₂. To determine whether this metabolic redirection impacted inflammation-associated intestinal tumorigenesis, Apc^Min/+ and Apc^Min/+:mPGES-1^-/- mice were exposed to DSS. DSS administration caused a reduction in the number of intestinal polyps only in Apc^Min/+:mPGES-1^-/- mice. These results demonstrate the importance of the balance of prostaglandins produced in the intestinal tract for maintaining intestinal homeostasis and impacting tumor development.