The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia
| Autor: | Cristhine Pastorini, Anli Chen, Daisy E. Conduah, Keith J. Breglio, Maria T. Abreu, Ruliang Xu, John P. Sotolongo, David Hsu, Lory Hayes, Yasmín Hernández, Ryan C. Ungaro, Masayuki Fukata |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Mice chemistry.chemical_compound 0302 clinical medicine Intestinal mucosa Medicine Intestinal Mucosa Prostaglandin E2 Mice Knockout 0303 health sciences Dextran Sulfate Gastroenterology General Medicine Colitis 3. Good health ErbB Receptors 030220 oncology & carcinogenesis Colonic Neoplasms Intercellular Signaling Peptides and Proteins Female lipids (amino acids peptides and proteins) medicine.symptom Signal Transduction Research Article medicine.drug EGF Family of Proteins medicine.medical_specialty Azoxymethane Inflammation Amphiregulin Dinoprostone 03 medical and health sciences Internal medicine Animals lcsh:RC799-869 Cell Proliferation Glycoproteins 030304 developmental biology Dose-Response Relationship Drug business.industry medicine.disease Mice Inbred C57BL Toll-Like Receptor 4 Disease Models Animal Endocrinology chemistry Cyclooxygenase 2 Dysplasia Prostaglandins TLR4 lcsh:Diseases of the digestive system. Gastroenterology business |
| Zdroj: | BMC Gastroenterology, Vol 10, Iss 1, p 82 (2010) BMC Gastroenterology |
| ISSN: | 1471-230X |
| Popis: | BackgroundWe have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE2and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE2is 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 PGE2in TLR4-/- mice to see if PGE2bypasses the protection from colitis-associated tumorigenesis.MethodMouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE2(high dose group, 200 μg, n = 8; and low dose group, 100 μg, n = 6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE2during DSS treatment (200 μg, n = 5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.ResultsIn 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 PGE2treatment 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 PGE2treatment. Endogenous prostanoid synthesis was differentially affected by PGE2treatment during acute and recovery phases of colitis. Exogenous administration of PGE2increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE2treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.ConclusionsThese results highlight the importance of PGE2as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis. |
| Databáze: | OpenAIRE |
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