Tomato Lycopene Extract Prevents Lipopolysaccharide-Induced NF-κB Signaling but Worsens Dextran Sulfate Sodium-Induced Colitis in NF-κBEGFP Mice

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.
PLoS ONE (Impact Factor: 3.23). 02/2009; 4(2):e4562. DOI: 10.1371/journal.pone.0004562
Source: PubMed


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-κBEGFP 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-κB signaling. In vitro, TLE blocked LPS-induced IκBα degradation, RelA translocation, NF-κB 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-κBEGFP mice compared to control diet as measured by weight loss, colonoscopic analysis and histological scores. In contrast, TLE-fed IL-10−/−;NF-κBEGFP mice displayed decreased colonic EGFP expression compared to control diet. IL-6, TNFα, and MCP-1 mRNA expression were increased in the colon of TLE-fed, DSS-exposed NF-κBEGFP 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-κB signaling, but aggravates DSS-induced colitis by enhancing epithelial cell apoptosis.

Download full-text


Available from: Hans Herfarth
  • Source
    • "The intestinal mucosa is composed of a simple columnar epithelium (enterocytes), covering the crypt/villus units and crypt units of the small intestine and colon, respectively123. This mucosal surface is continuously exposed to a multitude of factors derived from dietary456, foreign678910, and self sources611 that can result in disruption of the physical barrier79. Therefore, the intestinal mucosa must perform its physiologic function of nutrient absorption2 while maintaining the ability to sense and respond to intestinal injury67891012. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Toll-like receptors (TLRs) are innate receptors critical for host defense, and play a role in normal biological processes. For example, host DNA, a TLR9 ligand, stimulates epithelial repair following skin wounding. TLR signaling also plays a crucial role in regulating intestinal homeostasis. We therefore asked whether TLR9 is important for intestinal wound repair using a dextran sulfate sodium (DSS)-induced intestinal damage and repair model. We showed that TLR9-deficient mice are more susceptible to DSS, and exhibited delayed wound repair at both the clinical and histologic levels. TLR9-deficient mice showed reduced gene expression of hairy enhancer of split 1, an intestinal progenitor cell differentiation factor, and vascular endothelial growth factor, a growth factor important for epithelial cell restitution. Therefore, we conclude that TLR stimulation may play a normal role in regulating intestinal homeostasis and could potentially be a novel therapeutic target to enhance intestinal wound repair in inflammatory bowel diseases.
    Full-text · Article · Aug 2012 · Scientific Reports
  • Source
    • "Chemical transfer of electrons between compounds does not occur during the inflammatory response. Bioactive compounds inhibit inflammation mainly by modifying inflammatory signaling cascades or inflammatory transcription factors (Joo et al., 2009; Kim et al., 2004; Neuzil, Weber, & Kontush, 2001). Therefore, interactions between compounds during inflammation will not be as direct as those observed during lipid peroxidation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: a b s t r a c t Tomato foods contain bioactive compounds, such as lycopene, ascorbic acid and a-tocopherol, which are assumed to show synergistic effects. The aim of the study was to investigate this presumed synergy. The effect on lipid peroxidation and inflammation was assessed. Lipid peroxidation was effectively inhibited by combinations of the compounds compared to the single compounds. Synergy between the combina-tion of ascorbic acid and a-tocopherol was confirmed. Lycopene on its own effectively reduced inflamma-tion by inhibiting the release of TNF-a and stimulating IL-10 production. The combination of lycopene, ascorbic acid and a-tocopherol tended to display a synergistic interaction on IL-10 production. Our obser-vations highlight that lycopene mitigates inflammation, whereas ascorbic acid and a-tocopherol effi-ciently protect against lipid peroxidation. Both activities are complementary since they diminish the process of inflammation differently on different levels. In relation to health, this is an added value of fruit and vegetables such as tomato products that contain complementary bio-active compounds.
    Full-text · Article · Nov 2011 · Food Chemistry
  • Source
    • "One of the possible mechanisms for the protective activities of lycopene in smoke-related pathologies is by down-regulation of the cigarette smoke-stimulated inflammatory response [25], [26]. In fact, the carotenoid has been reported to inhibit pivotal pro-inflammatory mediators, including ROS [27] and cytokines [28] and to affect signal transduction pathways involved in inflammatory processes, including nicotinamide adenine dinucleotide phosphate oxidase oxidase [NADP(H)-oxidase] [28], MAPK [29], Akt/PI3K [30] and transcription factors, such as activator protein-1 (AP-1) [31] and NF-kB [31]–[35] and PPARγ cascade [28]. We recently reported that lycopene may inhibit ROS production, NOX-4 expression and cytokine release in human macrophages exposed to oxysterols [28]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Increasing evidence suggests that lycopene, the major carotenoid present in tomato, may be preventive against smoke-induced cell damage. However, the mechanisms of such a prevention are still unclear. The aim of this study was to investigate the role of lycopene on the production of the pro-inflammatory cytokine IL-8 induced by cigarette smoke and the possible mechanisms implicated. Therefore, human THP-1 macrophages were exposed to cigarette smoke extract (CSE), alone and following a 6-h pre-treatment with lycopene (0.5-2 µM). CSE enhanced IL-8 production in a time- and a dose-dependent manner. Lycopene pre-treatment resulted in a significant inhibition of CSE-induced IL-8 expression at both mRNA and protein levels. NF-kB controlled the transcription of IL-8 induced by CSE, since PDTC prevented such a production. Lycopene suppressed CSE-induced NF-kB DNA binding, NF-kB/p65 nuclear translocation and phosphorylation of IKKα and IkBα. Such an inhibition was accompanied by a decrease in CSE-induced ROS production and NOX-4 expression. Lycopene further inhibited CSE-induced phosphorylation of the redox-sensitive ERK1/2, JNK and p38 MAPKs. Moreover, the carotenoid increased PPARγ levels which, in turn, enhanced PTEN expression and decreased pAKT levels in CSE-exposed cells. Such effects were abolished by the PPARγ inhibitor GW9662. Taken together, our data indicate that lycopene prevented CSE-induced IL-8 production through a mechanism involving an inactivation of NF-kB. NF-kB inactivation was accompanied by an inhibition of redox signalling and an activation of PPARγ signalling. The ability of lycopene in inhibiting IL-8 production, NF-kB/p65 nuclear translocation, and redox signalling and in increasing PPARγ expression was also found in isolated rat alveolar macrophages exposed to CSE. These findings provide novel data on new molecular mechanisms by which lycopene regulates cigarette smoke-driven inflammation in human macrophages.
    Full-text · Article · May 2011 · PLoS ONE
Show more