23 research outputs found
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 <sub>2 </sub>and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE <sub>2 </sub>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 <sub>2 </sub>in TLR4-/- mice to see if PGE <sub>2 </sub>bypasses 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 <sub>2 </sub>(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 <sub>2 </sub>during 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 <sub>2 </sub>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 <sub>2 </sub>treatment. Endogenous prostanoid synthesis was differentially affected by PGE <sub>2 </sub>treatment during acute and recovery phases of colitis. Exogenous administration of PGE <sub>2 </sub>increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE <sub>2 </sub>treatment 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 <sub>2 </sub>as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.</p
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Innate Immunity and its Implications on Pathogenesis of Inflammatory Bowel Disease
This chapter contains sections titled:
Introduction
Overview of the innate immune system
Expression of TLRs in health and disease
General role of TLRs and Nods: maintenance of barrier function, induction of IgA and expression of antimicrobial peptides
Expression of Nods in health and disease
Link between innate immunity and adaptive immunity in the pathogenesis of IBD
Innate immunity links genetic susceptibility to IBD and commensal bacteria
Conclusion and implications for therapy of IBD
Reference
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S1287 Toll-Like Receptor 4 (TLR4) Differentially Regulates Epidermal Growth Factor (EGF)-Related Growth Factors in Response to Acute Intestinal Mucosal Injury
The Myeloid Differentiation Factor 88 (MyD88) Is Required for CD4 +
Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease (IBD). MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4+CD45Rb(high) T cells and/or CD4+CD45Rb(low)CD25+ regulatory T cells (Tregs) were isolated and adoptively transferred to RAG1−/− mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [(3)H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4+CD45Rb(high) T cells expressed TLR2, TLR4, TLR9, and TLR3 and TLR ligands could act as co-stimulatory molecules. MyD88−/− CD4+ T cells showed decreased proliferation compared with WT CD4+ T cells both in vivo and in vitro. CD4+CD45Rb(high) T cells from MyD88−/− mice did not induce wasting disease when transferred into RAG1−/− recipients. Lamina propria CD4+ T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88−/− cells than mice receiving WT cells. In vitro, MyD88−/− T cells were blunted in their ability to secrete IL-17 but not IFN-γ. Absence of MyD88 in CD4+CD45Rb(high) cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of IBD
The myeloid differentiation factor 88 (MyD88) is required for CD4+ T cell effector function in a murine model of inflammatory bowel disease
Abnormal T cell responses to commensal bacteria are involved in the pathogenesis of inflammatory bowel disease. MyD88 is an essential signal transducer for TLRs in response to the microflora. We hypothesized that TLR signaling via MyD88 was important for effector T cell responses in the intestine. TLR expression on murine T cells was examined by flow cytometry. CD4(+)CD45Rb(high) T cells and/or CD4(+)CD45Rb(low)CD25(+) regulatory T cells were isolated and adoptively transferred to RAG1(-/-) mice. Colitis was assessed by changes in body weight and histology score. Cytokine production was assessed by ELISA. In vitro proliferation of T cells was assessed by [(3)H]thymidine assay. In vivo proliferation of T cells was assessed by BrdU and CFSE labeling. CD4(+)CD45Rb(high) T cells expressed TLR2, TLR4, TLR9, and TLR3, and TLR ligands could act as costimulatory molecules. MyD88(-/-) CD4(+) T cells showed decreased proliferation compared with WT CD4(+) T cells both in vivo and in vitro. CD4(+)CD45Rb(high) T cells from MyD88(-/-) mice did not induce wasting disease when transferred into RAG1(-/-) recipients. Lamina propria CD4(+) T cell expression of IL-2 and IL-17 and colonic expression of IL-6 and IL-23 were significantly lower in mice receiving MyD88(-/-) cells than mice receiving WT cells. In vitro, MyD88(-/-) T cells were blunted in their ability to secrete IL-17 but not IFN-gamma. Absence of MyD88 in CD4(+)CD45Rb(high) cells results in defective T cell function, especially Th17 differentiation. These results suggest a role for TLR signaling by T cells in the development of inflammatory bowel disease
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92 T Cell Signaling Via the Toll-Receptor Associated Activator of Interferon (TRIF) Pathway Protects from the Development of Acute and Chronic Murine Colitis
S1287 Toll-Like Receptor 4 (TLR4) Differentially Regulates Epidermal Growth Factor (EGF)-Related Growth Factors in Response to Acute Intestinal Mucosal Injury
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146 The Role of Toll-Like Receptor 4 (TLR4) in Epithelial-Macrophage Cross-Talk in the Development of Intestinal Neoplasia
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S1649 The Role of Prostaglandin E2 (PGE2) in Toll-Like Receptor-4 (TLR4)-Mediated Colitis-Associated Neoplasia
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