Publications by authors named "Tobias Polte"

33 Publications

Wood emissions and asthma development: Results from an experimental mouse model and a prospective cohort study.

Environ Int 2021 Feb 18;151:106449. Epub 2021 Feb 18.

UFZ - Helmholtz Centre for Environmental Research Leipzig-Halle, Department of Environmental Immunology, Leipzig, Germany; Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, University of Leipzig, Leipzig, Germany. Electronic address:

Background: Increased use of renewable resources like sustainably produced wood in construction or for all sorts of long-lived products is considered to contribute to reducing society's carbon footprint. However, as a natural, biological material, wood and wood products emit specific volatile organic compounds (VOCs). Therefore, the evaluation of possible health effects due to wood emissions is of major interest.

Objectives: We investigated the effects of an exposure to multiple wood-related VOCs on asthma development.

Methods: A murine asthma model was used to evaluate possible allergic and inflammatory effects on the lung after short- or long-term and perinatal exposure to pinewood or oriented strand board (OSB). In addition, wood-related VOCs were measured within the German prospective mother-child cohort LINA and their joint effect on early wheezing or asthma development in children until the age of 10 was estimated by Bayesian kernel machine regression (BKMR) stratifying also for family history of atopy (FHA).

Results: Our experimental data show that neither pinewood nor OSB emissions even at high total VOC levels and a long-lasting exposure period induce significant inflammatory or asthma-promoting effects in sensitized or non-sensitized mice. Moreover, an exposure during the vulnerable time window around birth was also without effect. Consistently, in our mother-child cohort LINA, an exposure to multiple wood-related VOCs during pregnancy or the first year of life was not associated with early wheezing or asthma development in children independent from their FHA.

Conclusion: Our findings indicate that emissions from wood and wood products at levels commonly occurring in the living environment do not exert adverse effects concerning wheezing or asthma development.
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http://dx.doi.org/10.1016/j.envint.2021.106449DOI Listing
February 2021

Phthalate Exposure During the Prenatal and Lactational Period Increases the Susceptibility to Rheumatoid Arthritis in Mice.

Front Immunol 2020 3;11:550. Epub 2020 Apr 3.

Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.

The prenatal and early postnatal period is highly sensitive to environmental exposures that may interfere with the developmental programming of the immune system leading to an altered disease risk in later life. To clarify the role of early influences in activation or exacerbation of autoimmune diseases like rheumatoid arthritis (RA) we investigated the effect of maternal exposure during the prenatal and lactational period of DBA/1 mice to the plasticizer benzyl butyl phthalate (BBP) on the development of RA in the offspring. Using a mild collagen-induced arthritis (CIA) model, maternal BBP-exposure increased both the prevalence and the severity of RA in the progeny compared to un-exposed dams. Additionally, maternal BBP exposure led to elevated serum IgG and IgG level in the offspring and increased the IFN-γ and IL-17 release from collagen-re-stimulated spleen cells. Transcriptome analysis of splenocytes isolated from 3-week-old pups before RA-induction revealed considerable changes in gene expression in the offspring from BBP-exposed dams. Among them were and , all genes that have previously been described as associated with RA pathology. In summary, our results demonstrate that perinatal exposure to BBP increases the susceptibility of the offspring to RA, probably via a phthalate-induced disturbed regulation of RA-relevant genes or signaling pathways.
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http://dx.doi.org/10.3389/fimmu.2020.00550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145968PMC
April 2020

Maternal paraben exposure triggers childhood overweight development.

Nat Commun 2020 02 11;11(1):561. Epub 2020 Feb 11.

Department for Environmental Immunology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany.

Parabens are preservatives widely used in consumer products including cosmetics and food. Whether low-dose paraben exposure may cause adverse health effects has been discussed controversially in recent years. Here we investigate the effect of prenatal paraben exposure on childhood overweight by combining epidemiological data from a mother-child cohort with experimental approaches. Mothers reporting the use of paraben-containing cosmetic products have elevated urinary paraben concentrations. For butyl paraben (BuP) a positive association is observed to overweight within the first eight years of life with a stronger trend in girls. Consistently, maternal BuP exposure of mice induces a higher food intake and weight gain in female offspring. The effect is accompanied by an epigenetic modification in the neuronal Pro-opiomelanocortin (POMC) enhancer 1 leading to a reduced hypothalamic POMC expression. Here we report that maternal paraben exposure may contribute to childhood overweight development by altered POMC-mediated neuronal appetite regulation.
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http://dx.doi.org/10.1038/s41467-019-14202-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012887PMC
February 2020

mediates the impact of prenatal bisphenol A exposure on long-term body weight development.

Clin Epigenetics 2018 20;10:58. Epub 2018 Apr 20.

1Department of Environmental Immunology, Helmholtz Centre for Environmental Research (UFZ), Leipzig, Germany.

Background: Exposure to endocrine-disrupting chemicals can alter normal physiology and increase susceptibility to non-communicable diseases like obesity. Especially the prenatal and early postnatal period is highly vulnerable to adverse effects by environmental exposure, promoting developmental reprogramming by epigenetic alterations. To obtain a deeper insight into the role of prenatal bisphenol A (BPA) exposure in children's overweight development, we combine epidemiological data with experimental models and BPA-dependent DNA methylation changes.

Methods: BPA concentrations were measured in maternal urine samples of the LINA mother-child-study obtained during pregnancy ( = 552), and BPA-associated changes in cord blood DNA methylation were analyzed by Illumina Infinium HumanMethylation450 BeadChip arrays ( = 472). Methylation changes were verified by targeted MassARRAY analyses, assessed for their functional translation by qPCR and correlated with children's body mass index (BMI) scores at the age of 1 and 6 years. Further, female BALB/c mice were exposed to BPA from 1 week before mating until delivery, and weight development of their pups was monitored ( ≥ 8/group). Additionally, human adipose-derived mesenchymal stem cells were treated with BPA during the adipocyte differentiation period and assessed for exposure-related epigenetic, transcriptional and morphological changes ( = 4).

Results: In prenatally BPA-exposed children two CpG sites with deviating cord blood DNA-methylation profiles were identified, among them a hypo-methylated CpG in the promoter of the obesity-associated mesoderm-specific transcript (. A mediator analysis suggested that prenatal BPA exposure was connected to cord blood promoter methylation and expression as well as BMI scores in early infancy. This effect could be confirmed in mice in which prenatal BPA exposure altered promoter methylation and transcription with a concomitant increase in the body weight of the juvenile offspring. An experimental model of in vitro differentiated human mesenchymal stem cells also revealed an epigenetically induced expression and enhanced adipogenesis following BPA exposure.

Conclusions: Our study provides evidence that mediates the impact of prenatal BPA exposure on long-term body weight development in offspring by triggering adipocyte differentiation.
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http://dx.doi.org/10.1186/s13148-018-0478-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910578PMC
May 2019

Spray-Dried Nanoparticle-in-Microparticle Delivery Systems (NiMDS) for Gene Delivery, Comprising Polyethylenimine (PEI)-Based Nanoparticles in a Poly(Vinyl Alcohol) Matrix.

Small 2018 03 12;14(12):e1701810. Epub 2018 Feb 12.

Rudolf Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, University of Leipzig, Haertelstrasse 16 - 18, Leipzig, D-04107, Germany.

Nucleic acid-based therapies rely on efficient formulations for nucleic acid protection and delivery. As nonviral strategies, polymeric and lipid-based nanoparticles have been introduced; however, biological efficacy and biocompatibility as well as poor storage properties due to colloidal instability and their unavailability as ready-to-use systems are still major issues. Polyethylenimine is the most widely explored and promising candidate for gene delivery. Polyethylenimine-based polyplexes and their combination with liposomes, lipopolyplexes, are efficient for DNA or siRNA delivery in vitro and in vivo. In this study, a highly potent spray-dried nanoparticle-in-microparticle delivery system is presented for the encapsulation of polyethylenimine-based polyplexes and lipopolyplexes into poly(vinyl alcohol) microparticles, without requiring additional stabilizing agents. This easy-to-handle gene delivery device allows prolonged nanoparticle storage and protection at ambient temperature. Biological analyses reveal further advantages regarding profoundly reduced cytotoxicity and enhanced transfection efficacies of polyethylenimine-based nanoparticles from the nanoparticle-in-microparticle delivery system over their freshly prepared counterparts, as determined in various cell lines. Importantly, this nanoparticle-in-microparticle delivery system is demonstrated as ready-to-use dry powder to be an efficient device for the inhalative delivery of polyethylenimine-based lipopolyplexes in vivo, as shown by transgene expression in mice after only one administration.
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http://dx.doi.org/10.1002/smll.201701810DOI Listing
March 2018

Early-onset childhood atopic dermatitis is related to NLRP2 repression.

J Allergy Clin Immunol 2018 04 9;141(4):1482-1485.e16. Epub 2017 Dec 9.

Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig, Leipzig, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2017.11.018DOI Listing
April 2018

Mold metabolites drive rheumatoid arthritis in mice via promotion of IFN-gamma- and IL-17-producing T cells.

Food Chem Toxicol 2017 Nov 19;109(Pt 1):405-413. Epub 2017 Sep 19.

UFZ - Helmholtz Centre for Environmental Research Leipzig-Halle, Department of Environmental Immunology, Leipzig, Germany; Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany. Electronic address:

Environmental factors have been discussed as triggers for autoimmune diseases like rheumatoid arthritis (RA). However, the role of chemical exposures in activation or exacerbation of RA is not clarified yet. Exposure of DBA/1 mice to the mold metabolites ochratoxin A (OTA) or deoxynivalenol (DON) increased the prevalence and the clinical severity of RA compared to un-exposed mice using an experimental collagen-induced arthritis model. Mycotoxin-exposed mice showed enhanced serum IgG1 and IgG2a levels and an elevated production of IL-1β and IL-6 in inflamed joints and of IFN-γ and IL-17 in splenocytes. Additionally, OTA and DON increased the release of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α in activated murine macrophages and supported the differentiation of naïve T cells into Th1 cells, while treatment of CD4+T cells with the supernatant from mycotoxin-exposed macrophages induced IL-17 production. Furthermore, exposure of mice to OTA or DON enhanced the gene expression of Stat1, Stat3 and Stat4 in the spleen while the collagen-induced increase of Socs1 and Socs3 was abolished. Our results demonstrate that mycotoxins increase the susceptibility to develop RA via an enhanced stimulation of macrophages and promotion of Th1/Th17 cell differentiation by induction of Stat signalling pathways and down-regulation of the Socs-mediated feedback inhibition.
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http://dx.doi.org/10.1016/j.fct.2017.09.027DOI Listing
November 2017

Syndecan-1 regulates dendritic cell migration in cutaneous hypersensitivity to haptens.

Exp Dermatol 2017 11 29;26(11):1060-1067. Epub 2017 Aug 29.

Department of Dermatology, Venerology and Allergology, Universitätsklinikum Leipzig, Leipzig, Germany.

In human dendritic cells (DCs), we previously demonstrated in vitro that syndecan-1 (SDC1) is downregulated during maturation correlating with enhanced motility. We investigated the effects of SDC1 on DC migration in vivo during TNCB(2,4,6-trinitro-1-chlorobenzene)-induced cutaneous hypersensitivity reaction (CHS) in mice. We show that DC in SDC1-deficient mice migrated faster and at a higher rate to lymph nodes draining the hapten-painted skin. Adoptive transfer of SDC1-deficient hapten- and fluorochrome-labelled DC into wild-type (WT) mice led to increased and faster migration of DC to paracortical lymph nodes, and to a stronger CHS compared to WT DC. In SDC1-/- mice, CCR7 remains longer on the DC surface within the first 15-minutes maturation (after LPS-induced maturation). In addition, a time-dependent upregulation of CCL2, CCL3, VCAM1 and talin was found during maturation in SDC1-/- DC. However, no difference in T-cell-stimulating capacity of SDC1-deficient DC was found compared to WT DC. Mechanistically, SDC1-deficient DC showed enhanced migration towards CCL21 and CCL19. This may result from functional overexpression of CCR7 in SDC1-/- DC. Increased and accelerated migration of otherwise functionally intact SDC1-deficient DC leads to an exacerbated CHS. Based on our results, we conclude that SDC1 on DC negatively regulates DC migration.
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http://dx.doi.org/10.1111/exd.13374DOI Listing
November 2017

Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications.

J Allergy Clin Immunol 2018 02 6;141(2):741-753. Epub 2017 Apr 6.

Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany; Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany. Electronic address:

Background: Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children because of exposure to plasticizers, such as phthalates, findings of previous studies are inconsistent and lack mechanistic information.

Objective: We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations.

Methods: Phthalate metabolites were measured within the prospective mother-child cohort Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk (LINA) and correlated with asthma development in the children. A murine transgenerational asthma model was used to identify involved pathways.

Results: In LINA maternal urinary concentrations of mono-n-butyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine transgenerational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by BBP-induced global DNA hypermethylation in CD4 T cells of the offspring because treatment with a DNA-demethylating agent alleviated exacerbation of allergic airway inflammation. Thirteen transcriptionally downregulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor zinc finger protein 1 (Zfpm1) emerged as a potential mediator of the enhanced susceptibility for T2-driven allergic asthma.

Conclusion: These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in T2 differentiation through epigenetic alterations.
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http://dx.doi.org/10.1016/j.jaci.2017.03.017DOI Listing
February 2018

From the exposome to mechanistic understanding of chemical-induced adverse effects.

Environ Int 2017 Feb 8;99:97-106. Epub 2016 Dec 8.

US EPA, National Center for Computational Toxicology, Research Triangle Park, NC 27711, USA.

The exposome encompasses an individual's exposure to exogenous chemicals, as well as endogenous chemicals that are produced or altered in response to external stressors. While the exposome concept has been established for human health, its principles can be extended to include broader ecological issues. The assessment of exposure is tightly interlinked with hazard assessment. Here, we explore if mechanistic understanding of the causal links between exposure and adverse effects on human health and the environment can be improved by integrating the exposome approach with the adverse outcome pathway (AOP) concept that structures and organizes the sequence of biological events from an initial molecular interaction of a chemical with a biological target to an adverse outcome. Complementing exposome research with the AOP concept may facilitate a mechanistic understanding of stress-induced adverse effects, examine the relative contributions from various components of the exposome, determine the primary risk drivers in complex mixtures, and promote an integrative assessment of chemical risks for both human and environmental health.
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http://dx.doi.org/10.1016/j.envint.2016.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116522PMC
February 2017

Allergen-Induced IL-6 Regulates IL-9/IL-17A Balance in CD4+ T Cells in Allergic Airway Inflammation.

J Immunol 2016 10 29;197(7):2653-64. Epub 2016 Aug 29.

Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, 04103 Leipzig, Germany; Department of Environmental Immunology, UFZ-Helmholtz Center for Environmental Research, 04318 Leipzig, Germany;

IL-9-secreting Th9 cells have been considered to play a pivotal role in the pathogenesis of atopic diseases. To what extent IL-9-producing cells are induced or regulated by sensitization with naturally occurring allergens is not yet clear. Naturally occurring allergens are capable of inducing IL-6 production in dendritic cells (DCs). Whether allergen-induced IL-6 supports a Th9 subtype by increasing IL-9 production, as observed in in vitro studies, or rather favors Th17 differentiation is not finally resolved. Therefore, in the present study we have investigated the impact of IL-6 on the Th9/Th17 balance depending on the predominant cytokine milieu and, additionally, in vivo using a DC-driven murine asthma model. In vitro, IL-6 increases Th9 cells under strong IL-4 and TGF-β activation, whereas under moderate IL-4 and TGF-β activation the presence of IL-6 shifts naive CD4(+) cells to Th17 cells. To induce allergic airway inflammation, OVA-pulsed DCs from IL-6-deficient or wild-type donors were adoptively transferred into BALB/c mice. Recipients receiving IL-6-producing wild-type DCs showed a significant decrease of Th9- and IL-4-producing Th2 cells but an increase of Th17 cells in lung tissue in comparison with recipients sensitized with IL-6-deficient DCs. Our data suggest that the IL-6-mediated reduction of Th2-related IL-4 leads to a decline of the Th9 immune response and allows Th17 differentiation.
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http://dx.doi.org/10.4049/jimmunol.1501599DOI Listing
October 2016

Environment-induced epigenetic reprogramming in genomic regulatory elements in smoking mothers and their children.

Mol Syst Biol 2016 Mar 24;12(3):861. Epub 2016 Mar 24.

Department of Environmental Immunology, Helmholtz Centre for Environmental Research Leipzig - UFZ, Leipzig, Germany

Epigenetic mechanisms have emerged as links between prenatal environmental exposure and disease risk later in life. Here, we studied epigenetic changes associated with maternal smoking at base pair resolution by mapping DNA methylation, histone modifications, and transcription in expectant mothers and their newborn children. We found extensive global differential methylation and carefully evaluated these changes to separate environment associated from genotype-related DNA methylation changes. Differential methylation is enriched in enhancer elements and targets in particular "commuting" enhancers having multiple, regulatory interactions with distal genes. Longitudinal whole-genome bisulfite sequencing revealed that DNA methylation changes associated with maternal smoking persist over years of life. Particularly in children prenatal environmental exposure leads to chromatin transitions into a hyperactive state. Combined DNA methylation, histone modification, and gene expression analyses indicate that differential methylation in enhancer regions is more often functionally translated than methylation changes in promoters or non-regulatory elements. Finally, we show that epigenetic deregulation of a commuting enhancer targeting c-Jun N-terminal kinase 2 (JNK2) is linked to impaired lung function in early childhood.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812527PMC
http://dx.doi.org/10.15252/msb.20156520DOI Listing
March 2016

Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation.

Nat Commun 2015 Jul 13;6:7554. Epub 2015 Jul 13.

Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig 04103, Germany.

Syndecan-4 (SDC4), expressed on dendritic cells (DCs) and activated T cells, plays a crucial role in DC motility and has been shown as a potential target for activated T-cell-driven diseases. In the present study, we investigate the role of SDC4 in the development of T-helper 2 cell-mediated allergic asthma. Using SDC4-deficient mice or an anti-SDC4 antibody we show that the absence or blocking of SDC4 signalling in ovalbumin-sensitized mice results in a reduced asthma phenotype compared with control animals. Most importantly, even established asthma is significantly decreased using the anti-SDC4 antibody. The disturbed SDC4 signalling leads to an impaired motility and directional migration of antigen-presenting DCs and therefore, to a modified sensitization leading to diminished airway inflammation. Our results demonstrate that SDC4 plays an important role in asthma induction and indicate SDC4 as possible target for therapeutic intervention in this disease.
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http://dx.doi.org/10.1038/ncomms8554DOI Listing
July 2015

The G protein-coupled receptor P2Y14 influences insulin release and smooth muscle function in mice.

J Biol Chem 2014 Aug 3;289(34):23353-66. Epub 2014 Jul 3.

From the Institute of Biochemistry, Integrated Research and Treatment Center for Adiposity Diseases.

UDP sugars were identified as extracellular signaling molecules, assigning a new function to these compounds in addition to their well defined role in intracellular substrate metabolism and storage. Previously regarded as an orphan receptor, the G protein-coupled receptor P2Y14 (GPR105) was found to bind extracellular UDP and UDP sugars. Little is known about the physiological functions of this G protein-coupled receptor. To study its physiological role, we used a gene-deficient mouse strain expressing the bacterial LacZ reporter gene to monitor the physiological expression pattern of P2Y14. We found that P2Y14 is mainly expressed in pancreas and salivary glands and in subpopulations of smooth muscle cells of the gastrointestinal tract, blood vessels, lung, and uterus. Among other phenotypical differences, knock-out mice showed a significantly impaired glucose tolerance following oral and intraperitoneal glucose application. An unchanged insulin tolerance suggested altered pancreatic islet function. Transcriptome analysis of pancreatic islets showed that P2Y14 deficiency significantly changed expression of components involved in insulin secretion. Insulin secretion tests revealed a reduced insulin release from P2Y14-deficient islets, highlighting P2Y14 as a new modulator of proper insulin secretion.
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http://dx.doi.org/10.1074/jbc.M114.580803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156089PMC
August 2014

Lifetime-dependent effects of bisphenol A on asthma development in an experimental mouse model.

PLoS One 2014 20;9(6):e100468. Epub 2014 Jun 20.

UFZ - Helmholtz Centre for Environmental Research Leipzig-Halle, Department of Environmental Immunology, Leipzig, Germany; Department of Dermatology, Venerology and Allergology, Leipzig University Medical Center, Leipzig, Germany.

Background: Environmental factors are thought to contribute significantly to the increase of asthma prevalence in the last two decades. Bisphenol A (BPA) is a xenoestrogen commonly used in consumer products and the plastic industry. There is evidence and an ongoing discussion that endocrine disruptors like BPA may affect human health and also exert alterations on in the immune system. The aim of this study was to investigate age-dependent effects of BPA on the asthma risk using a murine model to explain the controversial results reported till date.

Methods: BALB/c mice were exposed to BPA via the drinking water for different time periods including pregnancy and breastfeeding. To induce an asthma phenotype, mice were sensitized to ovalbumin (OVA), followed by an intrapulmonary allergen challenge.

Results: BPA exposure during pregnancy and breastfeeding had no significant effect on asthma development in the offspring. In contrast, lifelong exposure from birth until the last antigen challenge clearly increased eosinophilic inflammation in the lung, airway hyperreactivity and antigen-specific serum IgE levels in OVA-sensitized adult mice compared to mice without BPA exposure. Surprisingly, BPA intake during the sensitization period significantly reduced the development of allergic asthma. This effect was reversed in the presence of a glucocorticoid receptor antagonist.

Conclusions: Our results demonstrate that the impact of BPA on asthma risk is strongly age-dependent and ranges from asthma-promoting to asthma-reducing effects. This could explain the diversity of results from previous studies regarding the observed health impact of BPA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100468PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065062PMC
February 2015

Generation of IL-8 and IL-9 producing CD4⁺ T cells is affected by Th17 polarizing conditions and AHR ligands.

Mediators Inflamm 2014 20;2014:182549. Epub 2014 Feb 20.

UFZ-Helmholtz Centre for Environmental Research Leipzig, Department of Environmental Immunology, Permoserstrasse, 04318 Leipzig, Germany.

The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells under in vitro conditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR) has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.
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http://dx.doi.org/10.1155/2014/182549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945483PMC
December 2014

Therapeutic potential of the peptide leucine arginine as a new nonplant bowman-birk-like serine protease inhibitor.

J Med Chem 2013 Sep 29;56(17):6732-44. Epub 2013 Aug 29.

Interdisciplinary Center of Clinical Research, University of Leipzig , Leipzig, Germany.

The peptide leucine arginine (pLR) belongs to a new class of cyclic peptides isolated from frog skin. Its primary sequence is similar to the reactive loop of plant Bowman-Birk inhibitors (BBI), and the recently discovered circular sunflower trypsin inhibitor-1 (SFTI-1). The conformational properties of pLR in solution were determined by NMR spectroscopy and revealed excellent structural similarity to BBI and SFTI-1. Moreover, pLR is a highly potent trypsin inhibitor, with Ki values in the nanomolar range, and, due to its small size, a potential inhibitor of the serine protease tryptase. Since tryptase plays a crucial role in the development of allergic airway inflammation, the therapeutic potential of pLR in a murine asthma model was investigated. Treatment of ovalbumin-sensitized mice with pLR during allergen challenge reduced the acute asthma phenotype. Most importantly, application even at the end of a long-lasting chronic asthma model decreased the development of chronic airway inflammation and tissue remodeling.
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http://dx.doi.org/10.1021/jm4005362DOI Listing
September 2013

Volatile organic compounds enhance allergic airway inflammation in an experimental mouse model.

PLoS One 2012 3;7(7):e39817. Epub 2012 Jul 3.

Department of Environmental Immunology, UFZ-Helmholtz Centre for Environmental Research Leipzig-Halle, Leipzig, Germany.

Background: Epidemiological studies suggest an association between exposure to volatile organic compounds (VOCs) and adverse allergic and respiratory symptoms. However, whether VOCs exhibit a causal role as adjuvants in asthma development remains unclear.

Methods: To investigate the effect of VOC exposure on the development of allergic airway inflammation Balb/c mice were exposed to VOCs emitted by new polyvinylchloride (PVC) flooring, sensitized with ovalbumin (OVA) and characterized in acute and chronic murine asthma models. Furthermore, prevalent evaporated VOCs were analyzed and mice were exposed to selected single VOCs.

Results: Exposure of mice to PVC flooring increased eosinophilic lung inflammation and OVA-specific IgE serum levels compared to un-exposed control mice. The increased inflammation was associated with elevated levels of Th2-cytokines. Long-term exposure to PVC flooring exacerbated chronic airway inflammation. VOCs with the highest concentrations emitted by new PVC flooring were N-methyl-2-pyrrolidone (NMP) and 2,2,4-trimethyl-1,3-pentanediol diisobutyrate (TXIB). Exposure to NMP or TXIB also increased the allergic immune response in OVA-sensitized mice. In vitro or in vivo exposure to NMP or TXIB reduced IL-12 production in maturing dendritic cells (DCs) and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. At higher concentrations both VOCs induced oxidative stress demonstrated by increased isoprostane and glutathione-S-transferase-pi1 protein levels in the lung of non-sensitized mice. Treatment of PVC flooring-exposed mice with N-acetylcysteine prevented the VOC-induced increase of airway inflammation.

Conclusions: Our results demonstrate that exposure to VOCs may increase the allergic immune response by interfering with DC function and by inducing oxidative stress and has therefore to be considerate as risk factor for the development of allergic diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0039817PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389035PMC
December 2012

Thy-1 (CD90) regulates the extravasation of leukocytes during inflammation.

Eur J Immunol 2011 Mar 25;41(3):645-56. Epub 2011 Jan 25.

Department of Dermatology, Venerology and Allergology, Medical Faculty of Leipzig University, Leipzig, Germany.

Human Thy-1 (CD90) has been shown to mediate adhesion of inflammatory cells to activated microvascular endothelial cells via interaction with Mac-1 (CD11b/CD18) in vitro. Since there are no data showing the physiological relevance of Thy-1 for the recruitment of inflammatory cells in vivo, different inflammation models were investigated in Thy-1-deficient mice and littermate controls. In thioglycollate-induced peritonitis, the number of neutrophils and monocytes was significantly diminished in Thy-1-deficient mice. During acute lung inflammation, the extravasation of eosinophils and monocytes into the lung was significantly reduced in Thy-1-deficient mice. Moreover, during chronic lung inflammation, the influx of eosinophils and monocytes was also strongly decreased. These effects were independent of Thy-1 expression on T cells, as shown by the transplantation of WT BM into the Thy-1-deficient mice. In spite of the strong Thy-1 expression on T cells in the chimeric mice, the extravasation of the inflammatory cells in these mice was significantly diminished, compared to control mice. Finally, the altered number and composition of infiltrating leukocytes in Thy-1-deficient mice modified the chemokine/cytokine and protease expression at the site of inflammation. In conclusion, Thy-1 is involved in the control of inflammatory cell recruitment and, thus, also in conditioning the inflammatory microenvironment.
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http://dx.doi.org/10.1002/eji.201041117DOI Listing
March 2011

Involvement of the chemokine-like receptor GPR33 in innate immunity.

Biochem Biophys Res Commun 2010 May 23;396(2):272-7. Epub 2010 Apr 23.

Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.

Chemokine receptors control leukocyte chemotaxis and cell-cell communication but have also been associated with pathogen entry. GPR33, an orphan member of the chemokine-like receptor family, is a pseudogene in most humans. After the appearance of GPR33 in first mammalian genomes, this receptor underwent independent pseudogenization in humans, other hominoids and some rodent species. It was speculated that a likely cause of GPR33 inactivation was its interplay with a rodent-hominoid-specific pathogen. Simultaneous pseudogenization in several unrelated species within the last 1 million years (myr) caused by neutral drift appears to be very unlikely suggesting selection on the GPR33 null-allele. Although there are no signatures of recent selection on human GPR33 we found a significant increase in the pseudogene allele frequency in European populations when compared with African and Asian populations. Because its role in the immune system was still hypothetical expression analysis revealed that GPR33 is highly expressed in dendritic cells (DC). Murine GPR33 expression is regulated by the activity of toll-like receptors (TLR) and AP-1/NF-kappaB signaling pathways in cell culture and in vivo. Our data indicate an important role of GPR33 function in innate immunity which became dispensable during human evolution most likely due to past or balancing selection.
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http://dx.doi.org/10.1016/j.bbrc.2010.04.077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954049PMC
May 2010

Exposure to mycotoxins increases the allergic immune response in a murine asthma model.

Am J Respir Crit Care Med 2010 Jun 1;181(11):1188-99. Epub 2010 Mar 1.

UFZ - Helmholtz Centre for Environmental Research Leipzig-Halle, Department of Environmental Immunology, Leipzig, Germany.

Rationale: Epidemiological studies have shown that indoor molds are associated with increased prevalence and exacerbation of respiratory symptoms and asthma. Mycotoxins, secondary metabolites of molds, may contribute to these effects.

Objectives: To investigate the adjuvant activity of mycotoxins on allergic airway inflammation.

Methods: Balb/c mice were exposed via the airways to gliotoxin and via the intestine to patulin, sensitized with ovalbumin (OVA), and then analyzed in acute and chronic murine asthma models. In addition, the effect of mycotoxin exposure on dendritic cell (DC) function was investigated using murine bone marrow-derived DCs.

Measurements And Main Results: Exposure of mice to both mycotoxins enhanced dose-dependently airway hyperreactivity, eosinophilic lung inflammation, and OVA-specific IgE serum levels compared with mice that received only the antigen. These findings correlated with increased Th2 cytokine levels and decreased IFN-gamma production. Long-term mycotoxin exposure exacerbated chronic airway inflammation and airway remodeling. In vitro or in vivo mycotoxin exposure inhibited IL-12 production in maturing DCs and enhanced airway inflammation after adoptive DC transfer into Balb/c mice. Mycotoxin exposure enhanced OVA-induced lung lipid peroxidation and moderately increased isoprostane levels in naive mice. Treatment of mycotoxin-exposed DCs with the antioxidants N-acetylcysteine or glutathione ethyl ester restored IL-12 secretion and pretreatment of exposed mice with N-acetylcysteine prevented the mycotoxin-induced increase of airway inflammation and AHR.

Conclusions: Our results demonstrate that gliotoxin and patulin increase the allergic immune response in mice by modulating the Th1/Th2 balance via direct effects on IL-12 secretion in DCs and by inducing oxidative stress.
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http://dx.doi.org/10.1164/rccm.200909-1350OCDOI Listing
June 2010

Different role of CD30 in the development of acute and chronic airway inflammation in a murine asthma model.

Eur J Immunol 2009 Jul;39(7):1736-42

Department of Pediatric Pulmonology and Neonatology, Hannover Medical School, Germany.

CD30 is a costimulatory molecule of the TNF receptor superfamily, expressed on activated T and B cells. Previously, we have shown in a murine asthma model the crucial role of CD30 signaling for the development of this Th2-cell-mediated disease. In the present study, we investigated the role of CD30 in the maintenance of the immune response. In contrast to the acute model, in the chronic model CD30(-/-) mice developed a severe asthma-like phenotype with eosinophilic inflammation and high serum IgE levels. Collagen content, ECM protein deposition and proliferation of smooth muscle cells as signs for airway remodeling were equally increased in both CD30(-/-) and WT mice. Reduced expression of the costimulatory molecule OX40 on CD3(+) T cells in the acute and up-regulation in the chronic model indirectly supported a compensatory role of OX40 for CD30 signaling. In accordance, application of agonistic OX40 antibody restored the asthma phenotype in CD30(-/-) mice in the acute model, whereas chronic airway inflammation was reduced in the presence of an inhibitory anti-OX40 ligand antibody. These data demonstrate that the crucial role of CD30 signaling in the development of acute asthma may be taken over by other costimulatory molecules like OX40 after long-term exposure to the antigen.
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http://dx.doi.org/10.1002/eji.200839004DOI Listing
July 2009

Probiotic Escherichia coli Nissle 1917 suppresses allergen-induced Th2 responses in the airways.

Int Arch Allergy Immunol 2009 12;149(3):219-30. Epub 2009 Feb 12.

Center for Infectious Diseases, University of Würzburg, Würzburg, Germany.

Background: Recent clinical trials, epidemiological studies and animal experiments have suggested that probiotics may help suppress the development of allergic responses.

Objective: To investigate whether the application of the probiotic Escherichia coli strain Nissle 1917 (EcN) protects mice from developing ovalbumin (OVA)-specific T helper-2 responses in the airways.

Methods: OVA-specific Th2 responses were induced by 2 intraperitoneal (i.p.) injections with OVA/alum followed by 1 intranasal (i.n.) challenge with OVA. EcN was given orally during the entire sensitization and challenge period, together with OVA/alum during the i.p. sensitizations, or i.n. before or during the airway challenge with OVA.

Results: We found that when the bacteria were given together with OVA/alum airway eosinophilia, airway hyper-reactivity, goblet cell metaplasia and IL-5 levels in the bronchoalveolar lavage and mediastinal lymph node cell cultures were reduced. This effect was associated with increased numbers of IFN-gamma producing T helper-1 cells and IFN-gamma levels in the airways and strongly increased OVA-specific IgG(2a) titers in the serum. The suppressive effect on airway eosinophilia was dependent on IFN-gamma but not TLR-4. Applying EcN i.n. or orally did not reduce the development of allergen-specific Th2 responses.

Conclusions: Our results suggest that EcN can inhibit the development of allergic responses when the bacteria are present at the site of Th2 cell priming and that this immunomodulatory effect is due to a shift from Th2 to Th1 response. The data support the hypothesis that probiotics may help reduce allergic responses and that EcN may also be used as adjuvant therapy to induce allergen-specific Th1 responses.
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http://dx.doi.org/10.1159/000199717DOI Listing
July 2009

Allergy prevention starts before conception: maternofetal transfer of tolerance protects against the development of asthma.

J Allergy Clin Immunol 2008 Nov;122(5):1022-1030.e5

Department of Pediatrics, Division of Pediatric Pulmonology and Neonatology, Hannover Medical School, Hannover, Germany.

Background: Allergy prevention must start early because environmental exposures during pregnancy and young life determine disease risk.

Objective: In this study we analyzed whether prevention can start even earlier before conception by transfer of immunologic tolerance from the mother to the offspring preventing the offspring from having asthma.

Methods: BALB/c mice were orally tolerized with ovalbumin before conception by means of oral application of antigen. The offspring of tolerized and naive mothers were immunized with ovalbumin at 6 weeks and 4 months of age and analyzed in our murine asthma model.

Results: Although the offspring of naive mothers had an asthma-like phenotype, the offspring of tolerized mice were completely protected, even when immunized as late as 8 months after birth. Critically involved in the tolerance transfer was allergen-specific IgG, levels of which were increased in the sera of the mother, fetus, and pup and breast milk. FcRn(-/-) mice, which cannot transport IgG through the placenta, transferred tolerance to the offspring only when the missing diaplacental IgG transfer was compensated by IgG transfer through breast milk from tolerant mothers but not when weaned by naive wet nurses. Inhibition of IFN-gamma, produced by memory T cells in the offspring, abrogated the protective effect of maternal tolerance, demonstrating a crucial role for IFN-gamma in the maintenance of allergen-specific tolerance.

Conclusion: Our data show that maternal immunologic memory has a significant and persistent effect on the immune response of the offspring.
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http://dx.doi.org/10.1016/j.jaci.2008.09.014DOI Listing
November 2008

A gene-dosage effect for interleukin-4 receptor alpha-chain expression has an impact on Th2-mediated allergic inflammation during bronchopulmonary mycosis.

J Infect Dis 2008 Dec;198(11):1714-21

Institute of Immunology, College of Veterinary Medicine, University of Leipzig, An den Tierkliniken 11, Leipzig, Germany.

Interleukin (IL)-4 and IL-13 are key factors in the pathogenesis of bronchopulmonary mycosis induced in mice by infection with Cryptococcus neoformans. Both cytokines use the IL-4 receptor alpha-chain (IL-4Ralpha). In this study, we investigated the role played by IL-4Ralpha expression in susceptibility to pulmonary C. neoformans infection. IL-4Ralpha(-/-) mice were extremely resistant. To characterize the effect of IL-4Ralpha expression level on disease outcome, we generated IL-4Ralpha(+/-) first-generation (F1) mice. IL-4Ralpha(+/-) mice showed intermediate levels of IL-4Ralpha expression, in contrast to higher levels in wild-type mice and no expression in IL-4Ralpha(-/-) mice, indicating biallelic expression of the gene for IL-4Ralpha (Il4ra). Concomitant with intermediate IL-4Ralpha expression, F1 mice showed intermediate susceptibility associated with altered Th2/Th17 cytokine production, decreased immunoglobulin E levels, and reduced allergic inflammation. This indicates a gene-dosage effect of IL-4Ralpha expression on susceptibility to bronchopulmonary mycosis. These data provide the basis for novel therapies antagonizing IL-4Ralpha in Th2-related pulmonary infection and possibly also in asthma.
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http://dx.doi.org/10.1086/593068DOI Listing
December 2008

IL-13 induces disease-promoting type 2 cytokines, alternatively activated macrophages and allergic inflammation during pulmonary infection of mice with Cryptococcus neoformans.

J Immunol 2007 Oct;179(8):5367-77

Institute of Immunology, College of Veterinary Medicine, University of Leipzig, Leipzig, Germany.

In the murine model of Cryptococcus neoformans infection Th1 (IL-12/IFN-gamma) and Th17 (IL-23/IL-17) responses are associated with protection, whereas an IL-4-dependent Th2 response exacerbates disease. To investigate the role of the Th2 cytokine IL-13 during pulmonary infection with C. neoformans, IL-13-overexpressing transgenic (IL-13Tg(+)), IL-13-deficient (IL-13(-/-)), and wild-type (WT) mice were infected intranasally. Susceptibility to C. neoformans infection was found when IL-13 was induced in WT mice or overproduced in IL-13Tg(+) mice. Infected IL-13Tg(+) mice had a reduced survival time and higher pulmonary fungal load as compared with WT mice. In contrast, infected IL-13(-/-) mice were resistant and 89% of these mice survived the entire period of the experiment. Ag-specific production of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with a significant type 2 cytokine shift but only minor changes in IFN-gamma production. Consistent with enhanced type 2 cytokine production, high levels of serum IgE and low ratios of serum IgG2a/IgG1 were detected in susceptible WT and IL-13Tg(+) mice. Interestingly, expression of IL-13 by susceptible WT and IL-13Tg(+) mice was associated with reduced IL-17 production. IL-13 was found to induce formation of alternatively activated macrophages expressing arginase-1, macrophage mannose receptor (CD206), and YM1. In addition, IL-13 production led to lung eosinophilia, goblet cell metaplasia and elevated mucus production, and enhanced airway hyperreactivity. This indicates that IL-13 contributes to fatal allergic inflammation during C. neoformans infection.
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http://dx.doi.org/10.4049/jimmunol.179.8.5367DOI Listing
October 2007

Heme oxygenase-1 protein localizes to the nucleus and activates transcription factors important in oxidative stress.

J Biol Chem 2007 Jul 12;282(28):20621-33. Epub 2007 Apr 12.

Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA.

Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme degradation, is an integral membrane protein of the smooth endoplasmic reticulum. However, we detected an HO-1 immunoreactive signal in the nucleus of cultured cells after exposure to hypoxia and heme or heme/hemopexin. Under these conditions, a faster migrating HO-1 immunoreactive band was enriched in nuclear extracts, suggesting that HO-1 was cleaved to allow nuclear entry. This was confirmed by the absence of immunoreactive signal with an antibody against the C terminus and the lack of a C-terminal sequence by gas chromatographymass spectrometry. Incubation with leptomycin B prior to hypoxia abolished nuclear HO-1 and the faster migrating band on Western analysis, suggesting that this process was facilitated by CRM1. Furthermore, preincubation with a cysteine protease inhibitor prevented nuclear entry of green fluorescent protein-labeled HO-1, demonstrating that protease-mediated C-terminal cleavage was also necessary for nuclear transport of HO-1. Nuclear localization was also associated with reduction of HO activity. HO-1 protein, whether it was enzymatically active or not, mediated activation of oxidant-responsive transcription factors, including activator protein-1. Nevertheless, nuclear HO-1 protected cells against hydrogen peroxide-mediated injury equally as well as cytoplasmic HO-1. We speculate that nuclear localization of HO-1 protein may serve to up-regulate genes that promote cytoprotection against oxidative stress.
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http://dx.doi.org/10.1074/jbc.M607954200DOI Listing
July 2007

Helminth-derived products inhibit the development of allergic responses in mice.

Am J Respir Crit Care Med 2007 Feb 22;175(4):336-44. Epub 2006 Nov 22.

Center for Infectious Diseases, University of Würzburg, Würzburg, Germany.

Rationale: Epidemiological studies suggest that infections with helminths protect from the development of asthma. Supporting this view is our published finding that infection with Nippostrongylus brasiliensis decreased ovalbumin-induced Th2 responses in the lung of mice.

Objectives: To evaluate if N. brasiliensis excretory-secretory products also prevent the development of asthma.

Methods: Mice were immunized with ovalbumin/alum intraperitoneally in the absence or presence of helminthic products and then challenged intranasally with ovalbumin. Six days later, we analyzed if the mice developed Th2 responses in the lung.

Main Results: The application of the helminthic products together with ovalbumin/alum during the sensitization period totally inhibited the development of eosinophilia and goblet cell metaplasia in the airways and also strongly reduced the development of airway hyperreactivity. Allergen-specific IgG1 and IgE serum levels were also strongly reduced. These findings correlated with decreased levels of IL-4 and IL-5 in the airways in product-treated animals. The suppressive effects on the development of allergic responses were independent of the presence of Toll-like receptors 2 and 4, IFN-gamma, and most important, IL-10. Interestingly, suppression was still observed when the helminthic products were heated or treated with proteinase K. Paradoxically, we found that strong helminth product-specific Th2 responses were induced in parallel with the inhibition of ovalbumin-specific responses.

Conclusion: Our results suggest that helminths suppress the development of asthma by secreting substances that modulate allergic responses without affecting the generation of helminth-specific Th2 immunity. The identification of these products may lead to the design of novel therapeutic intervention strategies for the treatment of asthma.
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http://dx.doi.org/10.1164/rccm.200601-054OCDOI Listing
February 2007

Direct evidence for a critical role of CD30 in the development of allergic asthma.

J Allergy Clin Immunol 2006 Oct 6;118(4):942-8. Epub 2006 Sep 6.

Department of Pediatrics, Division of Pediatric Pulmonology and Neonatology, Medizinische Hochschule Hannover, Germany.

Background: CD30 is a costimulatory molecule belonging to the TNF receptor superfamily that is expressed on activated T and B cells. Several studies have demonstrated a positive correlation between expression of CD30 or increased levels of soluble CD30 and the development and severity of allergic diseases. However, thus far, the evidence for a role of CD30 in allergic diseases, such as asthma, is only indirect.

Objective: The aim of the study was to directly investigate the role of CD30 in a murine asthma model.

Methods: CD30-deficient (B6.129P2-Tnfrsf8(tm1Mak)/J) and wild-type (WT) mice were immunized to ovalbumin (OVA) to induce an asthma-like phenotype and compared in our murine asthma model. Moreover, CD30/CD30 ligand signaling was blocked in OVA-immunized WT animals by using mAbs against CD30 receptor and its ligand, CD153.

Results: The absence of CD30 in OVA-immunized CD30-deficient mice resulted in significantly reduced airway inflammation, serum IgE levels, and TH2 cytokine levels. The same effect was observed when CD30/CD153 signaling was blocked in OVA-immunized WT animals with mAbs against CD30 or CD30 ligand.

Conclusion: Our results directly demonstrate that CD30/CD153 interaction plays an important role in the induction of TH2 cell-mediated allergic asthma.

Clinical Implications: These findings provide evidence for a role of the costimulatory molecule CD30 in allergic asthma.
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http://dx.doi.org/10.1016/j.jaci.2006.07.014DOI Listing
October 2006

Suppression of UVA-mediated release of labile iron by epicatechin--a link to lysosomal protection.

Free Radic Biol Med 2006 Oct 17;41(8):1197-204. Epub 2006 Jun 17.

Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.

UVA (320-380 nm) radiation generates an oxidative stress in cells and leads to an immediate release of potentially damaging labile iron pools in human skin cells. Treatment of cultured skin fibroblasts for several hours with physiologically relevant concentrations of either epicatechin (EC), a flavonoid plant constituent present in foods, or methylated epicatechin (3'-O-methyl epicatechin, MeOEC), its major human metabolite, prevents this iron release. The similarity of the effectiveness of EC and MeOEC argues against chelation as the mechanism of iron removal. Evidence based on measurements of lysosomal integrity strongly supports the hypothesis that the catechins protect against lysosomal destruction by UVA. Such damage would normally lead to protease release, which has been previously shown to cause ferritin degradation and release of labile iron.
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http://dx.doi.org/10.1016/j.freeradbiomed.2006.06.008DOI Listing
October 2006