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

<p>Abstract</p> <p>Background</p> <p>We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE ₂and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE ₂is 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 ₂in TLR4-/- mice to see if PGE ₂bypasses the protection from colitis-associated tumorigenesis.</p> <p>Method</p> <p>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 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 PGE ₂during 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.</p> <p>Results</p> <p>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 ₂treatment 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 ₂treatment. Endogenous prostanoid synthesis was differentially affected by PGE ₂treatment during acute and recovery phases of colitis. Exogenous administration of PGE ₂increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE ₂treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.</p> <p>Conclusions</p> <p>These results highlight the importance of PGE ₂as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.</p

The complete mitochondrial genome of freshwater mussel Pronodularia japanensis (Gonideinae, Unionidae, Unionida) from Tochigi Prefecture, Japan, and its phylogenetic analysis

We have sequenced the female-type (F-type) complete mitochondrial genome of Pronodularia japanensis (Gonideinae, Unionidae, Unionida, Bivalvia) from Tochigi Prefecture, Japan. The complete F-type mitochondrial genome (16,803 bp; LC505454) contains 13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes. Molecular phylogenetic analyses using complete F-type mitochondrial genomes of 56 Unionida species revealed the phylogenetic position of P. japanensis in Unionidae. This study should be basic data to investigate the genetic diversity in this species

The complete mitochondrial genome of freshwater mussel Nodularia douglasiae (Unionidae) from Lake Kasumigaura, Japan, and its phylogenetic analysis

We have sequenced the female type (F-type) mitochondrial genome of Nodularia douglasiae (Unioninae, Unionidae, Unionida, Bivalvia) from Lake Kasumigaura, Japan, and inferred the Unioninae phylogeny using complete mitochondrial genome sequences. The complete F-type mitochondrial genome (15,779 bp; LC496352) contains 13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes. Molecular phylogenetic analyses using complete F-type mitochondrial genomes from 15 Unioninae species including N. douglasiae from China and Korea were performed. This study should be basic data to investigate the genetic diversity of freshwater mussel N. douglasiae

F-type complete mitochondrial genomes of two Hyriposis species, H. schlegelii and H. cumingii (Bivalvia; Unionoida; Unionidae) from Lake Kasumigaura, Japan, and its phylogenetic analysis

We have sequenced the female type (F-type) complete mitochondrial genomes of two Hyriposis species, H. schlegelii and H. cumingii (Gonideinae, Unionidae, Unionida, Bivalvia) from Lake Kasumigaura, Japan, and inferred the Unioninae phylogeny. Complete mitochondrial genomes (H. schlegelii, 15,954 bp, LC498622; H. cumingii, 15,961 bp, LC498621) contain 13 protein-coding genes (PCGs), 2 rRNA genes, and 22 tRNA genes. Molecular phylogenetic analyses using the 13 PCGs including the two species were performed. This study should be basic data to investigate the evolution of Gonideinae and genetic diversity of Hyriposis species in local populations

Role of Toll-like Receptors in Gastrointestinal Malignancies

Mounting evidence supports the tenet that innate immune responses to luminal microbes participate in the development of gastrointestinal malignancies. The gastrointestinal tract is relatively unique in that it has evolved in the presence of diverse enteric microflora. Intestinal flora is required to develop a normal adaptive immune response in the periphery. With the characterization of the innate immune system, we have begun to understand the adaptations the intestine has made to the microbiota. The interaction between the microbiota and the intestinal mucosa through toll-like receptors (TLRs) is required to maintain intestinal homeostasis. In particular, intestinal epithelial cells and lamina propria mononuclear cells such as antigen presenting cells and T cells must respond to breaches in the mucosal barrier by activating TLR-dependent pathways that result in increased epithelial proliferation, wound healing, and recruitment of acute inflammatory cells. In the setting of chronic inflammation such as Helicobacter pylori ( H. pylori ) infection in the stomach or idiopathic inflammatory bowel disease (IBD), the process of repair may eventually result in carcinogenesis. The following review highlights human and animal data that support a role for innate immune responses and TLRs specifically in promoting gastrointestinal malignancies. Candidate pathways linking TLRs to gastrointestinal malignancies include activation of NF-κB and cyclooxygenase-2 (Cox-2). Studying the link between innate immune signaling and gastrointestinal malignancies offers the possibility to identify novel ways to both prevent and treat gastrointestinal cancer

Pathogen recognition receptors, cancer and inflammation in the gut

The pathogen recognition receptors (PRRs) initiate immediate responses against infection and tissue damage to protect the host from microbial invasion. In response to mucosal damage, intestinal PRR signaling initiates damage repair processes. Recent advances appear to link PRR abnormalities and inflammatory as well as neoplastic intestinal disorders. Emerging evidence suggests a dual role of PRRs, in which they may simultaneously induce tumorigenesis and antitumor immunity. PRR may induce tumor cell proliferation by activating cell survival signaling mainly via NF-kappaB, but this signal can activate dendritic cells to promote antitumor immunity. TLR signaling within the tumor cells may result in evasion of immune surveillance, propagation of metastatic growth, or rather, induction of tumor cell apoptosis depending on ligands. Epithelial cells induce endogenous PRR ligands when damaged or during neoplastic transformation. Targeted manipulation of PRR signaling may provide emerging opportunities for the development of new therapeutic strategies for many gastrointestinal diseases

Toll-Like Receptor 4 Signaling Integrates Intestinal Inflammation with Tumorigenesis: Lessons from the Murine Model of Colitis-Associated Cancer

Chronic inflammation has long been implicated as a predisposition for cancer, but the underlying mechanism for how this occurs has remained obscure. Ulcerative colitis (UC) is a chronic inflammatory disorder of the large intestine which is known to be highly linked to colorectal cancer. During chronic inflammation the intestinal mucosa is in a constant cycle of injury and repair resulting in aberrant epithelial proliferation, a process that increases the risk of neoplastic transformation. In particular, the coexistence of commensal flora in the intestine plays an important role in the regulation of mucosal restitution after epithelial injury. It has become apparent that signaling through toll-like receptors (TLRs), the receptor family recognizing pathogen-associated molecular patterns, is crucial to intestinal epithelial proliferation and mucosal restitution. We have recently described two important downstream pathways underlying TLR4-mediated epithelial proliferation in a mouse model of colitis-associated cancer; i.e., cyclooxygenase 2 (COX-2)-mediated production of prostaglandin E2 (PGE2), and induction of specific ligands for epidermal growth factor receptor (EGFR). These two pathways are closely involved with mucosal levels of PGE2 and other prostanoids such as 15-deoxy-delta 12,14-prostaglandin-J2 (15d-PGJ2). Understanding the fine interplay between the TLR signaling and intestinal tumorigenesis in the setting of chronic inflammation can contribute to establishing a novel treatment strategy for inflammation-associated cancers