The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia

• Published in: BMC gastroenterology Vol. 10; no. 1; p. 82
• Main Authors: Hernandez, Yasmin, Sotolongo, John, Breglio, Keith, Conduah, Daisy, Chen, Anli, Xu, Ruliang, Hsu, David, Ungaro, Ryan, Hayes, Lory A, Pastorini, Cristhine, Abreu, Maria T, Fukata, Masayuki
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 16-07-2010; BioMed Central; BMC
• Subjects: Amphiregulin; Animals; Azoxymethane - adverse effects; Cell Proliferation - drug effects; Colitis - chemically induced; Colitis - physiopathology; Colonic Neoplasms - chemically induced; Colonic Neoplasms - physiopathology; Cyclooxygenase 2 - physiology; Dextran Sulfate - adverse effects; Dinoprostone - pharmacology; Dinoprostone - physiology; Disease Models, Animal; Dose-Response Relationship, Drug; EGF Family of Proteins; ErbB Receptors - physiology; Female; Glycoproteins - physiology; Intercellular Signaling Peptides and Proteins - physiology; Intestinal Mucosa - drug effects; Intestinal Mucosa - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Prostaglandins - physiology; Signal Transduction - physiology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - physiology
• DOI: 10.1186/1471-230x-10-82
• EISSN: 1471-230X

We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE 2 and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE 2 is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE 2 in TLR4-/- mice to see if PGE 2 bypasses the protection from colitis-associated tumorigenesis.
Mouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE 2 (high dose group, 200 microg, n = 8; and low dose group, 100 microg, n = 6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE 2 during DSS treatment (200 microg, n = 5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.
In control mice treated with PBS, the average number of tumors was greater in WT mice (n = 13) than in TLR4-/- mice (n = 7). High dose but not low dose PGE 2 treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/- mice developed dysplasia (tumors/animal: 0.4 +/- 0.2). By contrast, 75.0% (tumors/animal: 1.5 +/- 1.2, P < 0.05) of the high dose group and 33.3% (tumors/animal: 0.3 +/- 0.5) of the low dose group developed dysplasia in TLR4-/- mice. Tumor size was also increased by high dose PGE 2 treatment. Endogenous prostanoid synthesis was differentially affected by PGE 2 treatment during acute and recovery phases of colitis. Exogenous administration of PGE 2 increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE 2 treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.
These results highlight the importance of PGE 2 as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.