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Genome wide responses of murine lungs to dietary alpha-tocopherol.

ABSTRACT: Alpha-tocopherol (alpha-T) may affect biological processes by modulating mRNA concentrations. This study screened the responses of approximately 15,000 lung mRNAs to dietary alpha-T in mice. The lung was chosen as the target organ because it is subjected to cyclical variations in oxidant and inflammatory stressors and alpha-T has been implicated in their modulations. The analysis identified approximately 400 mRNAs sensitive to alpha-T status of lungs determined by dietary alpha-T. The female lung transcriptome appears to be more sensitive to the alpha-T status than that of the male lungs. Here, we focus on the induction of 13 cytoskeleton genes by dietary alpha-T because they were similarly induced in the male and the female lungs. Their inductions were confirmed by quantitative-real-time-polymerase chain reaction (qRT-PCR). Immunohistochemical analyses of three of the encoded proteins suggest that they are expressed in lung vasculature and alveolar regions. The data suggest that the lung alpha-T status may modulate cytoarchitecture of lungs.

SUBMITTER: Oommen S

PROVIDER: S-EPMC2782686 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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Genome wide responses of murine lungs to dietary alpha-tocopherol.

Oommen Saji S Vasu Vihas T VT Leonard Scott W SW Traber Maret G MG Cross Carroll E CE Gohil Kishorchandra K

Free radical research 20070101 1

Alpha-tocopherol (alpha-T) may affect biological processes by modulating mRNA concentrations. This study screened the responses of approximately 15,000 lung mRNAs to dietary alpha-T in mice. The lung was chosen as the target organ because it is subjected to cyclical variations in oxidant and inflammatory stressors and alpha-T has been implicated in their modulations. The analysis identified approximately 400 mRNAs sensitive to alpha-T status of lungs determined by dietary alpha-T. The female lun ...[more]

PMID: 17164183

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Project description:Backgroundα-Tocopherol (αT) in its natural form [2'R, 4'R, 8'R αT (RRR-αT)] is more bioactive than synthetic α-tocopherol (all rac-αT). All rac-αT is widely used in infant formulas, but its accretion in formula-fed infant brain is unknown.ObjectiveWe sought to compare αT and stereoisomer status in infant rhesus macaques (Macaca mulatta) fed infant formula (RRR-αT or all rac-αT) with a reference group fed a mixed diet of breast milk and maternal diet.MethodsFrom 1 d after birth until 6 mo of age, infants (n = 23) were either nursery reared and exclusively fed 1 of 2 formulas by staff personnel or were community housed with their mothers and consumed a mixed reference diet of breast milk (69 mL/d at 6 mo) transitioning to monkey diet at ∼2 mo (MF; n = 8). Formulas contained either 21 μmol RRR-αT/L (NAT-F; n = 8) or 30 μmol all rac-αT/L (SYN-F; n = 7). Total αT and αT stereoisomers were analyzed in breast milk at 2, 4, and 6 mo and in monkey plasma and liver and 6 brain regions at 6 mo of age. α-Tocopherol transfer protein (α-TTP), lipoprotein αT, and urinary α-carboxyethyl-hydroxychroman (α-CEHC) were measured. One-way ANOVA with Tukey's post-hoc test was used for analysis.ResultsAt study termination, plasma, liver, lipoprotein, and brain total αT did not differ between groups. However, the NAT-F-fed group had higher RRR-αT than the SYN-F-fed group (P < 0.01) and the MF group (P < 0.0001) in plasma (1.7- and 2.7-fold) and brain (1.5- and 2.5-fold). Synthetic αT 2R stereoisomers (SYNTH-2R) were generally 3- and 7-fold lower in brain regions of the NAT-F group compared with those of the SYN-F and MF groups (P < 0.05). SYNTH-2R stereoisomers were 2-fold higher in MF than SYN-F (P < 0.0001). The plasma percentage of SYNTH-2R was negatively correlated with the brain percentage of RRR-αT (r = -0.99, P < 0.0001). Brain αT profiles were not explained by α-TTP mRNA or protein expression. Urine α-CEHC was 3 times higher in the NAT-F than in the MF group (P < 0.01).ConclusionsConsumption of infant formulas with natural (NAT-F) compared with synthetic (SYN-F) αT differentially impacted brain αT stereoisomer profiles in infant rhesus macaques. Future studies should assess the functional implications of αT stereoisomer profiles on brain health.

Project description:BackgroundCytokines such as TNF-alpha and IL-1 beta are known for their contribution to inflammatory processes in liver. In contrast, the cytokine IL-17 has not yet been assigned a role in liver diseases. IL-17 can cooperate with TNF-alpha to induce a synergistic response on several target genes in different cell lines, but no data exist for primary hepatocytes. To enhance our knowledge on the impact of IL-17 alone and combined with TNF-alpha in primary murine hepatocytes a comprehensive microarray study was designed. IL-1 beta was included as this cytokine is suggested to act in a similar manner as the combination of TNF-alpha and IL-17, especially with respect to its role in mRNA stabilization.ResultsThe present microarray analysis demonstrates that primary murine hepatocytes responded to IL-17 stimulation by upregulation of chemokines and genes, which are functionally responsible to increase and sustain inflammation. Cxcl2, Nfkbiz and Zc3h12a were strongly induced, whereas the majority of the genes were only very moderately up-regulated. Promoter analysis revealed involvement of NF-kappaB in the activation of many genes. Combined stimulation of TNF-alpha/IL-17 resulted in enhanced induction of gene expression, but significantly synergistic effects could be applied only to a few genes, such as Nfkbiz, Cxcl2, Zc3h12 and Steap4. Comparison of the gene expression profile obtained after stimulation of TNF-alpha/IL-17 versus IL-1 beta proposed an "IL-1 beta-like effect" of the latter cytokine combination. Moreover, evidence was provided that modulation of mRNA stability may be a major mechanism by which IL-17 regulates gene expression in primary hepatocytes. This assumption was exemplarily proven for Nfkbiz mRNA for the first time in hepatocytes. Our studies also suggest that RNA stability can partially be correlated to the existence of AU rich elements, but further mechanisms like the RNase activity of the up-regulated Zc3h12a have to be considered.ConclusionsOur microarray analysis gives new insights in IL-17 induced gene expression in primary hepatocytes highlighting the crosstalk with the NF-kappaB signaling pathway. Gene expression profile suggests IL-17 alone and in concert with TNF-alpha a role in sustaining liver inflammatory processes. IL-17 might exceed this function by RNA stabilization.

Dataset Information

Genome wide responses of murine lungs to dietary alpha-tocopherol.

Publications

Genome wide responses of murine lungs to dietary alpha-tocopherol.

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