EP Receptor Expression in Human Intestinal Epithelium and Localization Relative to the Stem Cell Zone of the Crypts

Abstract

There is substantial evidence for PGE2 affecting intestinal epithelial proliferation. PGE2 is also reported to be involved in the regulation of growth and differentiation in adult stem cells, both effects mediated by binding to EP-receptors. We have used the Lgr5 as a marker to scrutinize EP-receptor and COX expression in human intestinal epithelial cells with focus on the stem cell area of the crypts. Normal tissue from ileum and colon, but also duodenal biopsies from patients with untreated celiac disease, were investigated by immunohistochemistry and RT-PCR. The combination of fresh flash-frozen tissue and laser microdissection made it possible to isolate RNA from the epithelial cell layer, only. In the small intestine, Lgr5 labels cells are in the +4 position, while in the colon, Lgr5 positive cells are localized to the crypt bottoms. Epithelial crypt cells of normal small intestine expressed neither EP-receptor mRNA nor COX1/2. However, crypt cells in tissue from patients with untreated celiac disease expressed EP2/4 receptor and COX1 mRNA. In the colon, the situation was different. Epithelial crypt cells from normal colon were found to express EP2/4 receptor and COX1/2 transcripts. Thus, there are distinct differences between normal human small intestine and colon with regard to expression of EP2/4 receptors and COX1/2. In normal colon tissue, PGE2-mediated signaling through EP-receptors 2/4 could be involved in regulation of growth and differentiation of the epithelium, while the lack of EP-receptor expression in the small intestinal tissue exclude the possibility of a direct effect of PGE2 on the crypt epithelial cells.

The Prostanoid EP4 Receptor and Its Signaling Pathway

“…The inflamed duodenal epithelium from patients with untreated celiac disease expressed EP4 and EP2 in crypt cells. On the other hand, the EP1 and EP3 receptors were not detected in intestinal epithelium (Olsen Hult et al, 2011).…”

“…In contrast to its abundant expression in the colon epithelium, the EP4 receptor was not found in the intestinal smooth muscle layer in mice, rats, or humans (Ding et al, 1997;Morimoto et al, 1997;Olsen Hult et al, 2011). Other EP receptors have been found in the muscle layer of the gastrointestinal tract.…”

“…The EP4 receptor is also highly expressed in the human, mouse, and rat colon Ding et al, 1997;Kabashima et al, 2002;Olsen Hult et al, 2011). A recent study examined the precise distribution of the EP receptors in the intestinal epithelium in humans (Olsen Hult et al, 2011).…”

Vitamin D, Inflammation, and Colorectal Cancer Progression: A Review of Mechanistic Studies and Future Directions for Epidemiological Studies

“…Effects of calcitriol on COX2 in colon cancer cells have not been reported, but are likely because the PG receptor EP2 is also present in colon cells (24).…”

Colonic Saturated Fatty Acid Concentrations and Expression of COX-1, but not Diet, Predict Prostaglandin E2in Normal Human Colon Tissue

“…We also quantified expression 15-prostaglandin dehydrogenase (15-PGDH, gene name HPGD) that catabolizes PGE 2 and is down-regulated during tumorigenesis (7). Finally, we quantified expression of PGE 2 receptor genes, PTGER2 and PTGER4, for the receptors EP2 and EP4 that are expressed in colon and have well-defined roles in colon inflammation (8). …”