We demonstrate that intestinal inflammation caused by high-fat diet is increased by the environmental contaminant benzoapyrene. Our in vivo results indicate that a high-fat diet (HFD) induces a ...pre-diabetic state in mice compared with animals fed normal chow. HFD increased IL-1betamRNA concentration in the jejunum, colon, and liver, and TNFalpha was increased in the colon and strongly increased in the liver. HFD also increased the expression of other genes related to type 2 diabetes, such as the uncoupling protein UCP2, throughout the bowel and liver, but not in the colon. The treatment of HFD with BaP enhanced the expression of IL-1beta in the liver and TNFalpha throughout the bowel and in the liver. Adding BaP to the diet also caused a significant decrease in the expression of the incretin glucagon-like peptide 1, which plays an important role in insulin secretion. Our results suggest that intestinal inflammation may be involved in the onset of type 2 diabetes and that chronic exposure to environmental polycyclic aromatic hydrocarbons can increase the risk of type 2 diabetes by inducing pro-inflammatory cytokine production.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
As described for a long time, carcinoma-derived Caco-2 cells form a polarized epithelium in culture, whereas HT29-D4 cells are nonpolarized and undifferentiated but can form a polarized monolayer ...when cultured in a galactose-supplemented medium. Using NF-κB translocation and IL-8 and ICAM-1 gene activation as an index, we have studied the relationship between the differentiation state and the cell response to cytokines. We found that differentiated Caco-2 and HT29-D4 cells were responsive to both cytokines TNFα- and IL-1β-mediated activation of NF-κB but that undifferentiated HT29-D4 cells were unresponsive to IL-1β. However, the expression of endogenous ICAM-1 and IL-8 genes was upregulated by these cytokines in either cell lines differentiated or not. Upregulation of ICAM-1 gene occurred when IL-1β or TNFα was added to the basal, but not apical surface of the differentiated epithelia. Finally, it appeared that in polarized HT29-D4 cells, the IL-1β-induced translocation of NF-κB was connected to PKCδ translocation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Epidemiological studies have associated environmental exposure to polychlorinated biphenyls (PCBs) with an increased risk of type 2 diabetes; however, little is known about the underlying mechanisms ...involved in the metabolic side-effects of PCB. Our study evaluated the transcriptional effects of a subchronic exposure (gavage at Day 0 and Day 15 with 10 or 100 mu mol/Kg bw) to PCB118 (dioxin-like PCB), PCB153 (non-dioxin-like PCB), or an equimolar mixture of PCB118 and PCB153 on various tissues (liver, visceral adipose tissue, muscle, and colon) in mice. Our results showed that a short-term exposure to PCB118 and/or PCB153 enhanced circulating triglyceride levels but did not affect glycemia. Among the studied tissues, we did not observe any modification of the expression of inflammation-related genes, such as cytokines or chemokines. The main transcriptional effects were observed in visceral adipose and liver tissues. We found a downregulation of lipin1 and glut4 expression in these two target organs. In adipose tissue, we also showed a downregulation of Agpat2, Slc25a1, and Fasn. All of these genes are involved in lipid metabolism and insulin resistance. In muscles, we observed an induction of CnR1 and Foxo3 expression, which may be partly involved in PCB metabolic effects. In summary, our results suggest that lipin1 and glut4, notably in adipose tissue, are the main targeted genes in PCB-induced metabolic disorders, however, further studies are required to fully elucidate the mechanisms involved.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Les Polychlorobiphenyls (PCBs) sont des polluants organiques persistants (POPs). L’exposition humaine à ces composés est associée à un accroissement du risque de développement du diabète de type 2 ...(DT2). D’autres composés présents dans l’alimentation, comme les hydrocarbures aromatic polycyclic (PAH) tel que le benzo (a) pyrene (BaP), sont des ligands du récepteur aryl-hydrocabures (AhR) et augmentent ce risque. Le premier travail rapporté est une étude in vitro, sur les 3T3-L1, des effets "cocktail" de l’exposition à des PCBs (PCB118 et 153) et au BaP. Sur ce modèle, il apparait que le BaP et les PCBs réduisent en partie l’expression des gènes de l’adipogénèse (ADGG) et stimulent l’expression des gènes de l’inflammation (INFG). La seconde étude réalisée chez la souris, a permis d’évaluer les effets "cocktail" d’une exposition chronique au PCB118 et au BaP. Des paramètres biochimiques et l’expression des ADGG et INFG ont été mesurés dans différents tissus. Après ingestion de BaP, l’expression de deux ADGG (Glut4 and Lipin1) et trois INFG (MCP1, CXCL10, IFNγ) sont augmentés dans le tissue adipeux. Ces effets sont soit abolis, soit réduits en réponse à une co-exposition simultanée avec le PCB118. Ceci indique que les effets de chacun des composés peuvent être masqués l’un par l’autre. Dans les autres tissus, on observe également une modulation globale négative par le PCB des effets du BaP. L’ensemble de ces résultats sont discutés en référence au risque de TD2 induits par les POPs, ainsi qu’aux cibles moléculaires potentielles du BaP comme AhR et des PCBs comme CAR et PXR. On discute du rôle possible de l’IFNγ produit par les cellules immunitaires associées au tissu adipeux
The Polychlorobiphenyls (PCBs) are one of the persistent organic pollutants (POPs). Human exposure to these compounds is associated with an increased risk of developing of type 2 diabetes (DT2). Other chemical compounds, such as polycyclic aromtic hydrocarbon (HAP) such as the benzo (a) pyrene (BaP), that presented in food chain are ligands of the aryl hydrocarbon receptor (AhR) and they increase this risk. The first work reported is an in vitro study on the model of pre-adipocyte, 3T3-L1, on the "cocktail" effects of co-exposure to PCBs (PCB118 and 153) and BaP. On this model, it appears that BaP and PCBs partially reduce the expression of genes related to adipogenesis (ADGG) and stimulate the expression of genes related to inflammation (INFG). The second study was conducted in vivo which allow us to evaluate the "cocktail" effects of a chronic exposure to PCB118 and BaP in mice. Biochemical parameters and the expression of ADGG and INFG were measured in different tissues. After the ingestion of BaP, expression of two ADGGs (Glut4 and Lipin1) and three INFGs (MCP1, CXCL10, IFNγ) were increased in the adipose tissue. These effects are either abolished or reduced in response to simultaneous co-exposure with PCB118. This indicates that the effects of each compounds can be masked by one another. In the other tissues, there is also a global negative modulation by PCB on the effects induced by BaP. All these results are discussed with reference to the risk of DT2 induced by POPs, as well as potential molecular targets of BaP (such as AhR) and PCBs (as CAR and PXR). The possible role of IFNγ, produced by the immune cells, associated with adipose tissue is discussed
Using constructs expressing the reporter gene under the control of the entire or deleted long terminal repeats (LTRs) of 1731, a Drosophila melanogaster retrotransposable element, we show that ...1731-LTR is activated by X-irradiation in a dose- and time-dependent manner, and that a sequence located in the U3 region of these LTRs is required. The cis-acting element conferring X-responsiveness shows similarities to kappaB (kappaB)-like binding sequence. In response to X-irradiation, S2 Drosophila cells produced an extracellular factor which activates the 1731-LTR in nonirradiated cells. This factor was detected both when transfected cells were cocultured with inducing cells and when a conditioned medium taken from irradiated cultures was added.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pretreatment of HT29-D4 epithelial adenocarcinoma colic cells with des-IGF-1 upregulated TNFα-mediated activation of IL-8 expression at different levels (protein, mRNA, and hnRNA). RNA transcription ...but not RNA stabilization was found to be involved. In this cell line, cooperation of NF-κB with other factors appeared essential for IL-8 expression. Indeed, TNFα-induced NF-κB translocation was not sufficient to support enhancement of the transcription and des-IGF-1 did not promote but partly inhibited both the TNFα-induced NF-κB activation and IκBα degradation through a PI-3K-dependent pathway. A CCAAT/enhancer binding protein (C/EBP) site located on the IL-8 gene enhancer cooperated with a NF-κB binding site and led to the upregulation of IL-8 expression. Binding of C/EBPα to this sequence disappeared in IGF-1 treated cells. This event may be important for the cross-talk between IGF-1- and TNFα-mediated pathways leading to the control of inflammatory processes and the decision concerning apoptosis or cell survival.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mn(2+) was found to induce adhesion of HT29-D4 adenoma carcinoma cells to fibrinogen (Fb). This was independent of the expression of the beta3 integrin subunit and involved endogenous alphavbeta6 but ...not alphavbeta5 integrin. Thus, addition of Mn(2+) led to a change in integrin alphavbeta6 specificity. Furthermore, Mn(2+) was found to strongly activate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the HT29-D4 cell line. As a MAPK inhibitor strongly reduced the Mn(2+)-induced cell adhesion to Fb, it is suggested that a link between MAPK activation and cell adhesion to Fb exists. Both expression and activity of matrix metalloproteinase-9 (MMP-9) were enhanced by Mn(2+) and this led to Fb processing. MMP inhibitors prevented Mn(2+)-mediated cell adhesion to Fb, leading us to suggest that Mn(2+) promoted convergent changes in integrin alphavbeta6 conformation and Fb structure through activation of ERK/MAPK and MMP-9. Finally, we found that Mn(2+) and activators of the ERK pathway cooperated in HT29-D4 cell adhesion to Fb. Such a process may be involved in bone metastasis of some cancer cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Mn
2+ was found to induce adhesion of HT29-D4 adenoma carcinoma cells to fibrinogen (Fb). This was independent of the expression of the
β3 integrin subunit and involved endogenous
αv
β6 but not
αv
β5 ...integrin. Thus, addition of Mn
2+ led to a change in integrin
αv
β6 specificity. Furthermore, Mn
2+ was found to strongly activate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the HT29-D4 cell line. As a MAPK inhibitor strongly reduced the Mn
2+-induced cell adhesion to Fb, it is suggested that a link between MAPK activation and cell adhesion to Fb exists. Both expression and activity of matrix metalloproteinase-9 (MMP-9) were enhanced by Mn
2+ and this led to Fb processing. MMP inhibitors prevented Mn
2+-mediated cell adhesion to Fb, leading us to suggest that Mn
2+ promoted convergent changes in integrin
αv
β6 conformation and Fb structure through activation of ERK/MAPK and MMP-9. Finally, we found that Mn
2+ and activators of the ERK pathway cooperated in HT29-D4 cell adhesion to Fb. Such a process may be involved in bone metastasis of some cancer cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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