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Tomato lycopene extract prevents lipopolysaccharide-induced NF-kappaB signaling but worsens dextran sulfate sodium-induced colitis in NF-kappaBEGFP mice.

Joo YE, Karrasch T, Mühlbauer M, Allard B, Narula A, Herfarth HH, Jobin C - PLoS ONE (2009)

Bottom Line: In vitro, TLE blocked LPS-induced IkappaBalpha degradation, RelA translocation, NF-kappaB transcriptional activity and MIP-2 mRNA accumulation in IEC-18 cells.Moreover, LPS-induced IL-12p40 gene expression was dose-dependently inhibited in TLE-treated splenocytes.These results indicate that TLE prevents LPS-induced proinflammatory gene expression by blocking of NF-kappaB signaling, but aggravates DSS-induced colitis by enhancing epithelial cell apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT

Background: The impact of tomato lycopene extract (TLE) on intestinal inflammation is currently unknown. We investigated the effect of TLE on lipopolysaccharide (LPS)-induced innate signaling and experimental colitis.

Methodology/principal findings: Mice were fed a diet containing 0.5 and 2% TLE or isoflavone free control (AIN-76). The therapeutic efficacy of TLE diet was assessed using dextran sulfate sodium (DSS) exposed mice and IL-10(-/-);NF-kappaB(EGFP) mice, representing an acute and spontaneous chronic colitis model respectively. A mini-endoscope was used to determine the extent of macroscopic mucosal lesions. Murine splenocytes and intestinal epithelial cells were used to determine the in vitro impact of TLE on LPS-induced NF-kappaB signaling. In vitro, TLE blocked LPS-induced IkappaBalpha degradation, RelA translocation, NF-kappaB transcriptional activity and MIP-2 mRNA accumulation in IEC-18 cells. Moreover, LPS-induced IL-12p40 gene expression was dose-dependently inhibited in TLE-treated splenocytes. Interestingly, DSS-induced acute colitis worsened in TLE-fed NF-kappaB(EGFP) mice compared to control diet as measured by weight loss, colonoscopic analysis and histological scores. In contrast, TLE-fed IL-10(-/-);NF-kappaB(EGFP) mice displayed decreased colonic EGFP expression compared to control diet. IL-6, TNFalpha, and MCP-1 mRNA expression were increased in the colon of TLE-fed, DSS-exposed NF-kappaB(EGFP) mice compared to the control diet. Additionally, caspase-3 activation and TUNEL positive cells were enhanced in TLE diet-fed, DSS-exposed mice as compared to DSS control mice.

Conclusions/ significance: These results indicate that TLE prevents LPS-induced proinflammatory gene expression by blocking of NF-kappaB signaling, but aggravates DSS-induced colitis by enhancing epithelial cell apoptosis.

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Related in: MedlinePlus

TLE worsens DSS-induced experimental colitis.(A) Weight lost in TLE or control diet-fed mice exposed to 3% DSS. Values are mean±SEM; n = 6 in each group. Data were analyzed by ANOVA and comparison between groups performed using the Mann-Whitney U test. Results are representative of 3 independent experiments. (B). Colonic inflammation visualized by colonoscopy after 4 d of 3% DSS-exposure. Representative images of 6 different mice are shown. (C) The Colons of NF-κBEGFP mice were imaged using an EGFP macroimaging system. Photomicrographs are shown on the left. Representative images of 6 different mice are shown. C, AIN76A diet.
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pone-0004562-g004: TLE worsens DSS-induced experimental colitis.(A) Weight lost in TLE or control diet-fed mice exposed to 3% DSS. Values are mean±SEM; n = 6 in each group. Data were analyzed by ANOVA and comparison between groups performed using the Mann-Whitney U test. Results are representative of 3 independent experiments. (B). Colonic inflammation visualized by colonoscopy after 4 d of 3% DSS-exposure. Representative images of 6 different mice are shown. (C) The Colons of NF-κBEGFP mice were imaged using an EGFP macroimaging system. Photomicrographs are shown on the left. Representative images of 6 different mice are shown. C, AIN76A diet.

Mentions: To test the therapeutic potential of TLE on intestinal inflammation, NF-κBEGFP mice were pre-fed TLE or AIN-76A (control; C) and then exposed to 3% DSS. Surprisingly, by d 4 TLE-fed mice showed enhanced weight loss compared to control diet-fed mice (Fig. 4A). Colonoscopic analysis demonstrated that TLE-fed mice exhibited increased colonic inflammation with prominent mucosal edema and spontaneous bleeding compared to DSS-exposed mice on the control diet (Fig. 4B). Accordingly, the colon of TLE-fed, DSS-exposed NF-κBEGFP mice displayed enhanced EGFP expression compared to control diet-fed mice (Fig. 4C). Histological evaluation of the colon of TLE-fed, DSS-exposed NF-κBEGFP mice revealed an increase in colonic inflammation compared to DSS-exposed, control diet-fed mice (P<0.05) (Fig. 5A). Colonic expression of IL-6, TNFα and MCP-1 mRNA were elevated in TLE-fed mice compared to control diet mice (Fig. 5B). We next tested whether TLE similarly exacerbates intestinal inflammation using the spontaneous Th1-mediated IL-10−/− model. Interestingly, TLE diet attenuated bacteria-induced colonic EGFP expression in IL-10−/−;NF-κBEGFP mice compared to control diet (Fig. 6A). In addition, histological score indicates a decrease in distal, proximal and cecal inflammation (Fig. 6B). These results showed that TLE do not increase NF-κB activity (EGFP expression) nor exacerbate colitis in this spontaneous model.


Tomato lycopene extract prevents lipopolysaccharide-induced NF-kappaB signaling but worsens dextran sulfate sodium-induced colitis in NF-kappaBEGFP mice.

Joo YE, Karrasch T, Mühlbauer M, Allard B, Narula A, Herfarth HH, Jobin C - PLoS ONE (2009)

TLE worsens DSS-induced experimental colitis.(A) Weight lost in TLE or control diet-fed mice exposed to 3% DSS. Values are mean±SEM; n = 6 in each group. Data were analyzed by ANOVA and comparison between groups performed using the Mann-Whitney U test. Results are representative of 3 independent experiments. (B). Colonic inflammation visualized by colonoscopy after 4 d of 3% DSS-exposure. Representative images of 6 different mice are shown. (C) The Colons of NF-κBEGFP mice were imaged using an EGFP macroimaging system. Photomicrographs are shown on the left. Representative images of 6 different mice are shown. C, AIN76A diet.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2642995&req=5

pone-0004562-g004: TLE worsens DSS-induced experimental colitis.(A) Weight lost in TLE or control diet-fed mice exposed to 3% DSS. Values are mean±SEM; n = 6 in each group. Data were analyzed by ANOVA and comparison between groups performed using the Mann-Whitney U test. Results are representative of 3 independent experiments. (B). Colonic inflammation visualized by colonoscopy after 4 d of 3% DSS-exposure. Representative images of 6 different mice are shown. (C) The Colons of NF-κBEGFP mice were imaged using an EGFP macroimaging system. Photomicrographs are shown on the left. Representative images of 6 different mice are shown. C, AIN76A diet.
Mentions: To test the therapeutic potential of TLE on intestinal inflammation, NF-κBEGFP mice were pre-fed TLE or AIN-76A (control; C) and then exposed to 3% DSS. Surprisingly, by d 4 TLE-fed mice showed enhanced weight loss compared to control diet-fed mice (Fig. 4A). Colonoscopic analysis demonstrated that TLE-fed mice exhibited increased colonic inflammation with prominent mucosal edema and spontaneous bleeding compared to DSS-exposed mice on the control diet (Fig. 4B). Accordingly, the colon of TLE-fed, DSS-exposed NF-κBEGFP mice displayed enhanced EGFP expression compared to control diet-fed mice (Fig. 4C). Histological evaluation of the colon of TLE-fed, DSS-exposed NF-κBEGFP mice revealed an increase in colonic inflammation compared to DSS-exposed, control diet-fed mice (P<0.05) (Fig. 5A). Colonic expression of IL-6, TNFα and MCP-1 mRNA were elevated in TLE-fed mice compared to control diet mice (Fig. 5B). We next tested whether TLE similarly exacerbates intestinal inflammation using the spontaneous Th1-mediated IL-10−/− model. Interestingly, TLE diet attenuated bacteria-induced colonic EGFP expression in IL-10−/−;NF-κBEGFP mice compared to control diet (Fig. 6A). In addition, histological score indicates a decrease in distal, proximal and cecal inflammation (Fig. 6B). These results showed that TLE do not increase NF-κB activity (EGFP expression) nor exacerbate colitis in this spontaneous model.

Bottom Line: In vitro, TLE blocked LPS-induced IkappaBalpha degradation, RelA translocation, NF-kappaB transcriptional activity and MIP-2 mRNA accumulation in IEC-18 cells.Moreover, LPS-induced IL-12p40 gene expression was dose-dependently inhibited in TLE-treated splenocytes.These results indicate that TLE prevents LPS-induced proinflammatory gene expression by blocking of NF-kappaB signaling, but aggravates DSS-induced colitis by enhancing epithelial cell apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.

ABSTRACT

Background: The impact of tomato lycopene extract (TLE) on intestinal inflammation is currently unknown. We investigated the effect of TLE on lipopolysaccharide (LPS)-induced innate signaling and experimental colitis.

Methodology/principal findings: Mice were fed a diet containing 0.5 and 2% TLE or isoflavone free control (AIN-76). The therapeutic efficacy of TLE diet was assessed using dextran sulfate sodium (DSS) exposed mice and IL-10(-/-);NF-kappaB(EGFP) mice, representing an acute and spontaneous chronic colitis model respectively. A mini-endoscope was used to determine the extent of macroscopic mucosal lesions. Murine splenocytes and intestinal epithelial cells were used to determine the in vitro impact of TLE on LPS-induced NF-kappaB signaling. In vitro, TLE blocked LPS-induced IkappaBalpha degradation, RelA translocation, NF-kappaB transcriptional activity and MIP-2 mRNA accumulation in IEC-18 cells. Moreover, LPS-induced IL-12p40 gene expression was dose-dependently inhibited in TLE-treated splenocytes. Interestingly, DSS-induced acute colitis worsened in TLE-fed NF-kappaB(EGFP) mice compared to control diet as measured by weight loss, colonoscopic analysis and histological scores. In contrast, TLE-fed IL-10(-/-);NF-kappaB(EGFP) mice displayed decreased colonic EGFP expression compared to control diet. IL-6, TNFalpha, and MCP-1 mRNA expression were increased in the colon of TLE-fed, DSS-exposed NF-kappaB(EGFP) mice compared to the control diet. Additionally, caspase-3 activation and TUNEL positive cells were enhanced in TLE diet-fed, DSS-exposed mice as compared to DSS control mice.

Conclusions/ significance: These results indicate that TLE prevents LPS-induced proinflammatory gene expression by blocking of NF-kappaB signaling, but aggravates DSS-induced colitis by enhancing epithelial cell apoptosis.

Show MeSH
Related in: MedlinePlus