The role of prostaglandin E2 (PGE2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia.

07:07 EDT 27th August 2014 | BioPortfolio

Summary of "The role of prostaglandin E2 (PGE2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia."


ABSTRACT:

BACKGROUND:
We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE2 and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE2 is the central factor downstream of TLR4 signaling that promote intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE2 in TLR4-/- mice to see if PGE2 bypasses the protection from colitis-associated tumorigenesis.
METHOD:
Mouse 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 ug, n=8; and low dose group, 100 ug, n=6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE2 during DSS treatment (200 ug, n=5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.
RESULTS:
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 PGE2 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 PGE2 treatment. Endogenous prostanoid synthesis was differentially affected by PGE2 treatment during acute and recovery phases of colitis. Exogenous administration of PGE2 increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE2 treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.
CONCLUSION:
These results highlight the importance of PGE2 as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.

Affiliation

Journal Details

This article was published in the following journal.

Name: BMC gastroenterology
ISSN: 1471-230X
Pages: 82

Links

PubMed Articles [19009 Associated PubMed Articles listed on BioPortfolio]

Prostaglandin modulates TLR3-induced cytokine expression in Human astroglioma cells.

Cyclooxygenase (COX) products and pattern recognition receptors are important modulators of neuroinflammation; however, the role of prostaglandins and toll-like receptor (TLR) signaling and the functi...

Toll-like Receptor 4 Is Essential to Preserving Cardiac Function and Survival in Low-grade Polymicrobial Sepsis.

Toll-like receptor 4 (TLR4), the receptor for endotoxin, mediates hyperinflammatory response and contributes to high mortality during both endotoxin shock and severe sepsis. However, little is known a...

Prostaglandin E2-induced inflammation: relevance of prostaglandin E receptors.

Prostaglandin E2 (PGE2) is one of the most typical lipid mediators produced from arachidonic acid (AA) by cyclooxygenase (COX) as the rate-limiting enzyme, and acts on four kinds of receptor subtypes...

In silico and Ex vivo approaches identify a role for toll-like receptor 4 in colorectal cancer.

Inflammation increases the risk of colorectal cancer (CRC). We and others have described a role for TLR4, the receptor for LPS, in colon cancer. To explore the relationships between TLR4 expression an...

TLR2/TLR4 heterodimer mediates Inflammatory Injury in Intracerebral hemorrhage.

Objective: Inflammatory injury plays a critical role in intracerebral hemorrhage (ICH)-induced secondary brain injury. However, the upstream events that initiate inflammatory responses following ICH r...

Clinical Trials [1964 Associated Clinical Trials listed on BioPortfolio]

Comparison of Misoprostol and Prostaglandin E2 (PGE2) Gel for Induction of Labour in Premature Rupture of Membranes at Term

The purpose of this study is to determine whether induction of labor with vaginal misoprostol application will result in fewer cesarean deliveries than vaginal PGE2 gel application in wome...

Efficacy of Ketorolac 0.4% in Prostaglandin Supression

A pilot study to evaluate the extent of PGE2 inhibition (mean aqueous values) by Ketorolac 0.04% following peripheral iridotomy

Headache Inducing Characteristics and Possible Changes in Cerebral Blood Flow After Administration of PGE2

Before, during and after intravenous administration of PGE2 we score/measure headache, rCBF, blood flow in the middle cerebral artery and diameter of superficial temporal artery and correl...

Urinary Prostaglandin E Metabolite (PGE-M), A Metabolite of Prostaglandin E2 (PGE2): A Novel Biomarker of Crohn's Disease Activity

The purpose of this study is to determine whether urinary PGE-M levels correlate with Crohn's disease activity and to compare how well urinary PGE-M correlates with other non-invasive biom...

Possible Relation of Toll-Like Receptors and Nitric Oxide to Chronic Lung Disease

The first objective of this study is to determine if increased expression of one or more members of the toll-like receptor (TLR) family of receptors that are found on inflammatory cells (p...

Medical and Biotech [MESH] Definitions

A pattern recognition receptor that forms heterodimers with TOLL-LIKE RECEPTOR 2.

A pattern recognition receptor that forms heterodimers with other TOLL-LIKE RECEPTORS. It interacts with multiple ligands including PEPTIDOGLYCAN, bacterial LIPOPROTEINS, lipoarabinomannan, and a variety of PORINS.

Cell surface receptors that bind prostaglandins with high affinity and trigger intracellular changes which influence the behavior of cells. Prostaglandin receptor subtypes have been tentatively named according to their relative affinities for the endogenous prostaglandins. They include those which prefer prostaglandin D2 (DP receptors), prostaglandin E2 (EP1, EP2, and EP3 receptors), prostaglandin F2-alpha (FP receptors), and prostacyclin (IP receptors).

A family of pattern recognition receptors characterized by an extracellular leucine-rich domain and a cytoplasmic domain that share homology with the INTERLEUKIN 1 RECEPTOR and the DROSOPHILA toll protein. Following pathogen recognition, toll-like receptors recruit and activate a variety of SIGNAL TRANSDUCING ADAPTOR PROTEINS.

The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activa

Search BioPortfolio: