Tag: Receptor

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A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk.

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A new regulatory variant in the interleukin-6 receptor gene associates with asthma risk.

Genes Immun. 2013 Aug 15;

Authors: Revez JA, Bain L, Chapman B, Powell JE, Jansen R, Duffy DL, Tung JY, AAGC Collaborators, Matheson MC, Marks GB, Hui J, Le Souëf P, Danoy P, Baltic S, Nyholt DR, Jenkins M, Hayden C, Beilby J, Cheah F, Madden PA, Heath AC, Hopper JL, Musk B, Leeder SR, Walters EH, James A, Jones G, Abramson MJ, Robertson CF, Dharmage SC, Brown MA, Thompson PJ, Penninx BW, Visscher PM, De Geus EJ, Boomsma DI, Hinds DA, Martin NG, Montgomery GW, Ferreira MA

Abstract
The main genetic determinant of soluble interleukin 6 receptor (sIL-6R) levels is the missense variant rs2228145 that maps to the cleavage site of IL-6R. For each Ala allele, sIL-6R serum levels increase by ?20?ng?ml(-1) and asthma risk by 1.09-fold. However, this variant does not explain the total heritability for sIL-6R levels. Additional independent variants in IL6R may therefore contribute to variation in sIL-6R levels and influence asthma risk. We imputed 471 variants in IL6R and tested these for association with sIL-6R serum levels in 360 individuals. An intronic variant (rs12083537) was associated with sIL-6R levels independently of rs4129267 (P=0.0005), a proxy single-nucleotide polymorphism for rs2228145. A significant and consistent association for rs12083537 was observed in a replication panel of 354 individuals (P=0.033). Each rs12083537:A allele increased sIL-6R serum levels by 2.4?ng?ml(-1). Analysis of mRNA levels in two cohorts did not identify significant associations between rs12083537 and IL6R transcription levels. On the other hand, results from 16?705 asthmatics and 30?809 controls showed that the rs12083537:A allele increased asthma risk by 1.04-fold (P=0.0419). Genetic risk scores based on IL6R regulatory variants may prove useful in explaining variation in clinical response to tocilizumab, an anti-IL-6R monoclonal antibody.Genes and Immunity advance online publication, 15 August 2013; doi:10.1038/gene.2013.38.

PMID: 23945879 [PubMed – as supplied by publisher]

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Pathway to asthma winds through Toll-like receptor 4 – BCM News


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Pathway to asthma winds through Toll-like receptor 4
BCM News
Asthma is part of a battle that takes place as the immune system marshals its forces to fight off an invading organism-or what mimics such invaders. The ensuing fight takes a significant toll on the human airway and lungs, often generating a violent …
Clues emerge to explain allergic asthmaScience News
Insights into Asthma, And Maybe the Hygiene HypothesisBioWorld Online

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Safety and efficacy of the prostaglandin D(2) receptor antagonist AMG 853 in asthmatic patients.

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Safety and efficacy of the prostaglandin D(2) receptor antagonist AMG 853 in asthmatic patients.

J Allergy Clin Immunol. 2012 Nov 19;

Authors: Busse WW, Wenzel SE, Meltzer EO, Kerwin EM, Liu MC, Zhang N, Chon Y, Budelsky AL, Lin J, Lin SL

Abstract
BACKGROUND: The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on T(H)2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2. OBJECTIVE: We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma. METHODS: Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting ?-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting ?-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV(1), symptom scores, rescue short-acting ?-agonist use, and exacerbations. RESULTS: Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, -0.492; range for AMG 853 groups [n = 317], -0.444 to -0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator. CONCLUSION: AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma.

PMID: 23174659 [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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Sphingosine-1-phosphate induced airway hyperreactivity in rodents is mediated by the S1P3 receptor.

Sphingosine-1-phosphate induced airway hyperreactivity in rodents is mediated by the S1P3 receptor.

J Pharmacol Exp Ther. 2012 May 8;

Authors: Trifilieff A, Fozard JR

Abstract
There is a need to better understand the mechanism of airway hyperreactivity, a key feature of asthma. Evidence suggests that sphingosine-1-phosphate (S1P) could be a major player in this phenomenon. The purpose of this work was to define the S1P receptor responsible for this phenomenon. We have studied, in the rat, the effect of two S1P synthetic receptor ligands, FTY720 (which in its phosphorylated form is a potent agonist at each S1P receptor except S1P2) and AUY954 (a highly selective S1P1 agonist) on lung function in vivo. This was complemented by in vitro studies using isolated trachea from the rat, the S1P3 receptor-deficient mouse and its wild type counterpart. Following oral administration, FTY720 induced a generalized airway hyperreactivity to a range of contractile stimuli. This was observed as early as one hour post dosing, lasted for at least 24 hours and was not subject to desensitization. In both the rat and wild type mouse isolated trachea, pre-incubation with the active phosphorylated metabolite of FTY720, induced hyperresponsiveness to 5-HT. This effect was not seen in the isolated tracheas from S1P3 receptor-deficient mice. AUY954, did not mimic the effect of FTY720 either in vivo or in vitro. Our data are consistent with activation of the S1P pathway inducing a generalized airway hyperreactivity in rats and mice that is mediated by the S1P3 receptor. S1P3 receptor antagonists might prove useful as new therapeutic strategies aimed at blocking the airway hyperreactivity observed in asthma.

PMID: 22570366 [PubMed – as supplied by publisher]

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