Cellular and molecular biology (Noisy-le-Grand, France), 2003
Single nucleotide polymorphisms (SNPs) in the gene encoding the interleukin-4 receptor alpha chai... more Single nucleotide polymorphisms (SNPs) in the gene encoding the interleukin-4 receptor alpha chain (IL-4R alpha) have been associated with IgE levels or clinical atopy in some populations. Two SNPs that encode S503P and Q576R in the intracytoplasmic domain of the receptor are associated with loss or gain of function, respectively. We investigated the frequency of these SNPs and their association with traits of allergic asthma in 36 unrelated subjects selected from a racially admixed, clinically ascertained study population with family histories of asthma. The frequency of the 1682 T to C substitution that encodes S503P was 0.11 (70 alleles analyzed, from 29 TT homozygotes and 6 TC heterozygotes). The frequency of the 1902 A to G substitution that encodes Q576R was 0.26 (68 alleles analyzed, from 20 AA homozygotes, 10 AG heterozygotes and 4 GG homozygotes). In this atopic admixed sample, no significant association was detected between the variant genotypes and serum IgE levels, perce...
Cellular and molecular biology (Noisy-le-Grand, France), 2003
Interleukin 10 (IL-10) may play an important anti-inflammatory and immunoregulatory role in asthm... more Interleukin 10 (IL-10) may play an important anti-inflammatory and immunoregulatory role in asthma. In this study, we investigated the role of a C to A substitution at position -627 of the IL-10 promoter, located in a necessary transcriptional region, which contains a number of putative transcriptional binding sites. The -627 nucleotide position is itself flanked by Sp-1 and ets-1 binding sites. We studied the allele frequency in 53 unrelated subjects from an admixed Caucasian, Asian and Pacific Islander group with personal or family histories of asthma. The frequency of homozygous C/C, heterozygous C/A, and homozygous A/A alleles at position -627 was 0.28, 0.44 and 0.28, respectively. In vitro assays indicated no differences between the C/C and A/A forms in binding transcriptional factors, especially Sp-1 factor, or in promoter activity. Moreover, in this selected population, there was no association between the C to A substitution and serum IL-10 levels. The mean level of IL-10 se...
Asthma can progress to subepithelial airway fibrosis, mediated in large part by transforming grow... more Asthma can progress to subepithelial airway fibrosis, mediated in large part by transforming growth factor- (TGF-). The scaffolding protein caveolin-1 (cav1) can inhibit the activity of TGF-, perhaps by forming membrane invaginations that enfold TGF- receptors. The study goals were 1) to evaluate how allergen challenge affects lung expression of cav1 and the density of caveolae in vivo 2) to determine whether reduced cav1 expression is mediated by interleukin (IL)-4 and 3) to measure the effects of decreased expression of cav1 on TGF- signaling. C57BL/6J, IL-4-deficient mice, and cav1-deficient mice, sensitized by intraperitoneal injections of phosphate-buffered saline or ovalbumin (OVA) at days 0 and 12, received intranasal phosphate-buffered saline or OVA challenges at days 24, 26, and 28. Additionally, another group of C57BL/6J mice received IL-4 by intratracheal instillation for 7 days. We confirmed that the OVA-allergen challenge increased eosinophilia and T-helper type 2-related cytokine levels (IL-4, IL-5, and IL-13) in bronchoalveolar lavage. Allergen challenge reduced lung cav1 mRNA abundance by 40%, cav1 protein by 30%, and the number of lung fibroblast caveolae by 50%. Administration of IL-4 in vivo also substantially decreased cav1 expression. In contrast, the allergen challenge did not decrease cav1 expression in IL-4deficient mice. The reduced expression of cav1 was associated with activation of TGF- signaling that was further enhanced in OVA-sensitized and challenged cav1-deficient mice. This study demonstrates a previously unknown modulation of TGF- signaling by IL-4, via cav1, suggesting novel therapeutic targets for controlling the effects of TGF- and thereby ameliorating pathological airway remodeling. . 2 The abbreviations used are: Th2, T-helper type 2; TGF, transforming growth factor; IL, interleukin; cav1, caveolin-1; PBS, phosphate-buffered saline; OVA, ovalbumin; BAL, bronchoalveolar lavage; STAT, signal transducers and activators of transcription. Downloaded from FIGURE 4. Comparison of trichrome staining of lung sections from PBS-and OVA-sensitized and challenged C57 and cav1⌬ mice. Comparison between OVA-challenged tissues illustrates the increased collagen deposition (blue stain) in cav1⌬ mice. Original magnification was ϫ200. The table in the lower part of the figure shows the results of the grading from parenchymal and peribronchial and/or perivascular collagen deposition.
Asthma is driven by allergic airway inflammation and involves increased levels of oxidative stres... more Asthma is driven by allergic airway inflammation and involves increased levels of oxidative stress. This has led to speculation that antioxidants like selenium (Se) may play important roles in preventing or treating asthma. We fed diets containing low (0.08 parts per million), medium (0.25 parts per million), or high (2.7 parts per million) Se to female C57BL/6 mice and used an established OVA challenge protocol to determine the relationship between Se intake and the development of allergic airway inflammation. Results demonstrated that mice fed medium levels of Se had robust responses to OVA challenge in the lung as measured by lung cytokine levels, airway cellular infiltrate, eosinophilia, serum anti-OVA IgE, airway hyperreactivity, goblet cell hyperplasia, and phosphorylated STAT-6 levels in the lung. In contrast, responses to OVA challenge were less robust in mice fed low or high levels of Se. In particular, mice fed low Se chow showed significantly lower responses compared with mice fed medium Se chow for nearly all readouts. We also found that within the medium Se group the expression of lung glutathione peroxidase-1 and liver selenoprotein P were increased in OVA-challenged mice compared with PBS controls. These data suggest that Se intake and allergic airway inflammation are not related in a simple dose-response manner, which may explain the inconsistent results obtained from previous descriptive studies in humans. Also, our results suggest that certain selenoproteins may be induced in response to Ag challenges within the lung.
Cellular and molecular biology (Noisy-le-Grand, France), 2003
Single nucleotide polymorphisms (SNPs) in the gene encoding the interleukin-4 receptor alpha chai... more Single nucleotide polymorphisms (SNPs) in the gene encoding the interleukin-4 receptor alpha chain (IL-4R alpha) have been associated with IgE levels or clinical atopy in some populations. Two SNPs that encode S503P and Q576R in the intracytoplasmic domain of the receptor are associated with loss or gain of function, respectively. We investigated the frequency of these SNPs and their association with traits of allergic asthma in 36 unrelated subjects selected from a racially admixed, clinically ascertained study population with family histories of asthma. The frequency of the 1682 T to C substitution that encodes S503P was 0.11 (70 alleles analyzed, from 29 TT homozygotes and 6 TC heterozygotes). The frequency of the 1902 A to G substitution that encodes Q576R was 0.26 (68 alleles analyzed, from 20 AA homozygotes, 10 AG heterozygotes and 4 GG homozygotes). In this atopic admixed sample, no significant association was detected between the variant genotypes and serum IgE levels, perce...
Cellular and molecular biology (Noisy-le-Grand, France), 2003
Interleukin 10 (IL-10) may play an important anti-inflammatory and immunoregulatory role in asthm... more Interleukin 10 (IL-10) may play an important anti-inflammatory and immunoregulatory role in asthma. In this study, we investigated the role of a C to A substitution at position -627 of the IL-10 promoter, located in a necessary transcriptional region, which contains a number of putative transcriptional binding sites. The -627 nucleotide position is itself flanked by Sp-1 and ets-1 binding sites. We studied the allele frequency in 53 unrelated subjects from an admixed Caucasian, Asian and Pacific Islander group with personal or family histories of asthma. The frequency of homozygous C/C, heterozygous C/A, and homozygous A/A alleles at position -627 was 0.28, 0.44 and 0.28, respectively. In vitro assays indicated no differences between the C/C and A/A forms in binding transcriptional factors, especially Sp-1 factor, or in promoter activity. Moreover, in this selected population, there was no association between the C to A substitution and serum IL-10 levels. The mean level of IL-10 se...
Asthma can progress to subepithelial airway fibrosis, mediated in large part by transforming grow... more Asthma can progress to subepithelial airway fibrosis, mediated in large part by transforming growth factor- (TGF-). The scaffolding protein caveolin-1 (cav1) can inhibit the activity of TGF-, perhaps by forming membrane invaginations that enfold TGF- receptors. The study goals were 1) to evaluate how allergen challenge affects lung expression of cav1 and the density of caveolae in vivo 2) to determine whether reduced cav1 expression is mediated by interleukin (IL)-4 and 3) to measure the effects of decreased expression of cav1 on TGF- signaling. C57BL/6J, IL-4-deficient mice, and cav1-deficient mice, sensitized by intraperitoneal injections of phosphate-buffered saline or ovalbumin (OVA) at days 0 and 12, received intranasal phosphate-buffered saline or OVA challenges at days 24, 26, and 28. Additionally, another group of C57BL/6J mice received IL-4 by intratracheal instillation for 7 days. We confirmed that the OVA-allergen challenge increased eosinophilia and T-helper type 2-related cytokine levels (IL-4, IL-5, and IL-13) in bronchoalveolar lavage. Allergen challenge reduced lung cav1 mRNA abundance by 40%, cav1 protein by 30%, and the number of lung fibroblast caveolae by 50%. Administration of IL-4 in vivo also substantially decreased cav1 expression. In contrast, the allergen challenge did not decrease cav1 expression in IL-4deficient mice. The reduced expression of cav1 was associated with activation of TGF- signaling that was further enhanced in OVA-sensitized and challenged cav1-deficient mice. This study demonstrates a previously unknown modulation of TGF- signaling by IL-4, via cav1, suggesting novel therapeutic targets for controlling the effects of TGF- and thereby ameliorating pathological airway remodeling. . 2 The abbreviations used are: Th2, T-helper type 2; TGF, transforming growth factor; IL, interleukin; cav1, caveolin-1; PBS, phosphate-buffered saline; OVA, ovalbumin; BAL, bronchoalveolar lavage; STAT, signal transducers and activators of transcription. Downloaded from FIGURE 4. Comparison of trichrome staining of lung sections from PBS-and OVA-sensitized and challenged C57 and cav1⌬ mice. Comparison between OVA-challenged tissues illustrates the increased collagen deposition (blue stain) in cav1⌬ mice. Original magnification was ϫ200. The table in the lower part of the figure shows the results of the grading from parenchymal and peribronchial and/or perivascular collagen deposition.
Asthma is driven by allergic airway inflammation and involves increased levels of oxidative stres... more Asthma is driven by allergic airway inflammation and involves increased levels of oxidative stress. This has led to speculation that antioxidants like selenium (Se) may play important roles in preventing or treating asthma. We fed diets containing low (0.08 parts per million), medium (0.25 parts per million), or high (2.7 parts per million) Se to female C57BL/6 mice and used an established OVA challenge protocol to determine the relationship between Se intake and the development of allergic airway inflammation. Results demonstrated that mice fed medium levels of Se had robust responses to OVA challenge in the lung as measured by lung cytokine levels, airway cellular infiltrate, eosinophilia, serum anti-OVA IgE, airway hyperreactivity, goblet cell hyperplasia, and phosphorylated STAT-6 levels in the lung. In contrast, responses to OVA challenge were less robust in mice fed low or high levels of Se. In particular, mice fed low Se chow showed significantly lower responses compared with mice fed medium Se chow for nearly all readouts. We also found that within the medium Se group the expression of lung glutathione peroxidase-1 and liver selenoprotein P were increased in OVA-challenged mice compared with PBS controls. These data suggest that Se intake and allergic airway inflammation are not related in a simple dose-response manner, which may explain the inconsistent results obtained from previous descriptive studies in humans. Also, our results suggest that certain selenoproteins may be induced in response to Ag challenges within the lung.
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