The role of PGE2 in intestinal inflammation and tumorigenesis

Abstract

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, ApcMin/+ and ApcMin/+:mPGES-1−/− mice were exposed to DSS. DSS administration caused a reduction in the number of intestinal polyps only in ApcMin/+: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.

Cytosolic phospholipase A2: physiological function and role in disease

“…Differences in toxicity of cPLA 2 ␣ WT and KO mice did not correlate with PGE 2 levels, but may have been due to greater mitochondrial toxicity in KO mice. In the DSS model, there was extensive damage in the colons of cPLA 2 ␣ KO mice that correlated with lower levels of PGs in colon tissue compared with DSS-treated WT mice ( 127 ). Mice defi cient in mPGES-1 also exhibited greater DSS toxicity in the colon, suggesting an important protective role for PGE 2 .…”

“…However, there is a role for cPLA 2 ␣ in protecting the GI tract of mice from chemical toxicity induced by COX inhibitors and dextran sodium sulfate (DSS) ( 126,127 ). Injury induced by COX inhibitors in cPLA 2 ␣ KO mice did not occur in the colon, but was extensive in the small intestine, the site of greatest drug absorption ( 126 ).…”

Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of β-catenin expression via EP3-4 receptor

“…Prostaglandin E2 (PGE2), a key product of cyclooxygenase-2, participates in the development of inflammatory reactions and in oncogenesis (3,4). PGE2 was able to promote tumor cell proliferation, migration, invasion and anti-apoptosis.…”

Pulsatilla koreanaAmeliorates Ddextran Sulfate Sodium-induced Ccolitis in Mice

“…It was reported that COX-2 is important inflammatory biomarkers involved in the development of UC (Agoff et al, 2000). Prostaglandin E 2 (PGE 2 ) is the important prostaglandin in the colon and is associated with colonic inflammation (Montrose et al, 2015).…”