Tag: Expression

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IL-13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide-hCAP18/LL-37 in bronchial epithelial cells.

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IL-13 exposure enhances vitamin D-mediated expression of the human cathelicidin antimicrobial peptide-hCAP18/LL-37 in bronchial epithelial cells.

Infect Immun. 2012 Oct 8;

Authors: Schrumpf JA, van Sterkenburg MA, Verhoosel RM, Zuyderduyn S, Hiemstra PS

Abstract
Vitamin D is an important regulator of the expression of antimicrobial peptides, and vitamin D deficiency is associated with respiratory infections. Regulating expression of antimicrobial peptides such as the human cathelicidin antimicrobial peptide (hCAP)18/LL-37 by vitamin D in bronchial epithelial cells requires local conversion of 25(OH)vitaminD(3) (25D(3)) into its bioactive metabolite 1,25(OH)(2)vitaminD(3) (1,25D(3)) by CYP27B1. Low circulating vitamin D-levels in childhood asthma are associated with more severe exacerbations, which are often associated with infections. Atopic asthma is accompanied by Th2 driven inflammation mediated by cytokines such as IL-4 and IL-13, and the effect of these cytokines on vitamin D metabolism and hCAP-18/LL-37 expression is unknown. Therefore we investigated this in well-differentiated bronchial epithelial cells. To this end, cells were treated with IL-13 with and without 25D(3) and expression of hCAP18/LL-37, CYP27B1, the 1,25D(3) inactivating enzyme CYP24A1, and vitamin D receptor was assessed by quantitative PCR. We show that IL-13 enhances the ability of 25D(3) to increase expression of hCAP18/LL-37 and CYP24A1. In addition, exposure to IL-13 resulted in increased CYP27B1 expression, whereas VDR expression was not significantly affected. The enhancing effect of IL-13 on 25D(3)-mediated expression of hCAP18/LL-37 was further confirmed using SDS-PAGE Western Blot and immunofluorescence staining. In conclusion, we demonstrate that IL-13 induces vitamin D(-)dependent hCAP18/LL-37 expression, most likely by increasing CYP27B1. These data suggest that Th2 cytokines regulate the vitamin D metabolic pathway in bronchial epithelial cells.

PMID: 23045480 [PubMed – as supplied by publisher]

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Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset.

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Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset.

Thorax. 2012 Sep 26;

Authors: Coleman JM, Naik C, Holguin F, Ray A, Ray P, Trudeau JB, Wenzel SE

Abstract
BACKGROUND: Eosinophilic inflammation is implicated in asthma. Eotaxin 1-3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed. OBJECTIVE: To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma. METHODS: Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1-3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation. RESULTS: Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma. CONCLUSIONS: Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity.

PMID: 23015684 [PubMed – as supplied by publisher]

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A2B Adenosine Receptor Expression by Myeloid Cells Is Proinflammatory in Murine Allergic-Airway Inflammation.

A2B Adenosine Receptor Expression by Myeloid Cells Is Proinflammatory in Murine Allergic-Airway Inflammation.

J Immunol. 2012 Sep 5;

Authors: Belikoff BG, Vaickus LJ, Sitkovsky M, Remick DG

Abstract
Asthma is a chronic condition with high morbidity and healthcare costs, and cockroach allergens are an established cause of urban pediatric asthma. A better understanding of cell types involved in promoting lung inflammation could provide new targets for the treatment of chronic pulmonary disease. Because of its role in regulating myeloid cell-dependent inflammatory processes, we examined A(2B) R expression by myeloid cells in a cockroach allergen model of murine asthma-like pulmonary inflammation. Both systemic and myeloid tissue-specific A(2B) R deletion significantly decreased pulmonary inflammatory cell recruitment, airway mucin production, and proinflammatory cytokine secretion after final allergen challenge in sensitized mice. A(2B) R deficiency resulted in a dramatic reduction on Th2-type airways responses with decreased pulmonary eosinophilia without augmenting neutrophilia, and decreased lung IL-4, IL-5, and IL-13 production. Chemokine analysis demonstrated that eotaxin 1 and 2 secretion in response to repeated allergen challenge is myeloid cell A(2B) R dependent. In contrast, there were no differences in the levels of the CXC chemokines keratinocyte-derived chemokine and MIP-2 in the myeloid cell A(2B) R-deficient mice, strengthening A(2B) R involvement in the development of Th2-type airways inflammation. Proinflammatory TNF-?, IFN-?, and IL-17 secretion were also reduced in systemic and myeloid tissue-specific A(2B) R deletion mouse lines. Our results demonstrate Th2-type predominance for A(2B) R expression by myeloid cells as a mechanism of development of asthma-like pulmonary inflammation.

PMID: 22956582 [PubMed – as supplied by publisher]

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1?,25-Dihydroxyvitamin D3 promotes CD200 expression by human peripheral and airway-resident T cells.

1?,25-Dihydroxyvitamin D3 promotes CD200 expression by human peripheral and airway-resident T cells.

Thorax. 2012 Feb 14;

Authors: Dimeloe S, Richards DF, Urry ZL, Gupta A, Stratigou V, Farooque S, Saglani S, Bush A, Hawrylowicz CM

Abstract
BackgroundCD200, a cell-surface immunoglobulin-like molecule expressed by immune and stromal cells, dampens the pro-inflammatory activity of tissue-resident innate cells via its receptor, CD200R. This interaction appears critical for peripheral immune tolerance, particularly in the airways where excessive inflammation is undesirable. Vitamin D contributes to pulmonary health and promotes regulatory immune pathways, therefore its influence on CD200 and CD200R was investigated.MethodsCD200 and CD200R expression were assessed by qPCR and immunoreactivity of human lymphoid, myeloid and epithelial cells following 1?,25-dihydroxyvitamin D3 (1?,25VitD3) exposure in vitro and in peripheral T cells following 1?,25VitD3 oral ingestion in vivo. The effect of 1?25VitD3 was also assessed in human airway-resident cells.Results1?25VitD3 potently upregulated CD200 on peripheral human CD4+ T cells in vitro, and in vivo there was a trend towards upregulation in healthy, but not asthmatic individuals. CD200R expression was not modulated in any cells studied. CD200 induction was observed to a lesser extent in CD8+ T cells and not in B cells or airway epithelium. T cells isolated from the human airway also responded strongly to 1?25VitD3 to upregulate CD200.ConclusionsThe capacity of 1?,25-dihydroxyvitamin D3 to induce CD200 expression by peripheral and respiratory tract T cells identifies an additional pathway via which vitamin D can restrain inflammation in the airways to maintain respiratory health.

PMID: 22334534 [PubMed – as supplied by publisher]

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Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1).

Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1).

PLoS One. 2011;6(12):e29523

Authors: Anedda F, Zucchelli M, Schepis D, Hellquist A, Corrado L, D’Alfonso S, Achour A, McInerney G, Bertorello A, Lördal M, Befrits R, Björk J, Bresso F, Törkvist L, Halfvarson J, Kere J, D’Amato M

Abstract
BACKGROUND: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02).
PRINCIPAL FINDINGS: we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk.
SIGNIFICANCE: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.

PMID: 22216302 [PubMed – in process]

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“Asthma expression of allergy in respiratory system” – The Hindu


The Hindu

“Asthma expression of allergy in respiratory system”
The Hindu
There is no training or fellowship offered in India for studying allergies, said R.Sridharan, Consultant Allergist – Asthma Specialist. “Many doctors approach asthma as a respiratory condition but I approach it as an expression of an allergy in the …
Not a cracker of a time for asthmaticsTimes of India

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Altered expression of microRNA in the airway wall in chronic asthma: miR-126 … – 7thSpace Interactive (press release)

Altered expression of microRNA in the airway wall in chronic asthma: miR-126 …
7thSpace Interactive (press release)
In a mouse model, we have previously shown that miRNAs are potentially important therapeutic targets in allergic asthma, because inhibition of miR-126, one of a small subset of miRNAs upregulated in the airway wall, effectively suppressed Th2-driven …

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