Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus.

Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus. Research Abstract Details 

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Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus. Abstract Text:

Natalie Smith,Claudia A Browning,Nathalie Duroudier,Ceri Stewart,Samantha Peel,Caroline Swan,Ian P Hall,Ian Sayers,Natalie Smith,Claudia A Browning,Nathalie Duroudier,Ceri Stewart,Samantha Peel,Caroline Swan,Ian P Hall,Ian Sayers,Natalie Smith,Claudia A Browning,Nathalie Duroudier,Ceri Stewart,Samantha Peel,Caroline Swan,Ian P Hall,Ian Sayers,Natalie Smith,Claudia A Browning,Nathalie Duroudier,Ceri Stewart,Samantha Peel,Caroline Swan,Ian P Hall,Ian Sayers,

BACKGROUND: Airway hyper-responsiveness (AHR) is a key feature of asthma and a causal relationship between airway inflammation and AHR has been identified. The aim of the current study was to clarify the effect of proinflammatory cytokines and asthma medication on primary human airway smooth muscle (ASM) inositol phosphate (IPx) signalling and define the regulatory loci involved. METHODS: Primary Human ASM cells were isolated from explants of trachealis muscle from individuals with no history of respiratory disease. The effect of cytokine or asthma medication on histamine or bradykinin induced IPx signalling was assessed by [3H] inositol incorporation. Quantitative Real Time PCR was used to measure mRNA levels of receptors and downstream signalling components. Transcriptional mechanisms were explored using a combination of 5'Rapid Amplification of cDNA Ends (5'RACE) and promoter-reporter techniques. RESULTS: Treatment of Human ASM cells with IL-13, IFN gamma or salmeterol for 24 hours lead to a modest augmentation of histamine induced IPx responses (144.3 +/- 9.3, 126.4 +/- 7.5 and 117.7 +/- 5.2%, p < 0.05). Similarly, TNFalpha, IFN gamma or salmeterol treatment augmented bradykinin induced IPx responses (127.4 +/- 8.3, 128.0 +/- 8.4 and 111.7 +/- 5.0%, P < 0.05). No treatment significantly influenced sodium fluoride induced IPx responses suggesting regulation occurs at the receptor locus. Analyses of mRNA expression of components of the IPx pathway i.e. H1 Histamine Receptor (HRH1), B2 Bradykinin Receptor (BDKRB2), G alpha q/11 and PLC-beta1 identified that a significant induction of receptor mRNA (>2 fold) was a feature of these responses explaining the cytokine and spasmogen specificity. The HRH1 and BDKRB2 promoter regions were mapped in ASM and promoter-reporter analyses identified that salmeterol can induce HRH1 (>2 fold) and BDKRB2 (2-5 fold) transcription. The effect of cytokines on HRH1 and BDKRB2 promoter-reporter expression suggested a more complex regulation of mRNA expression involving additional loci to the core promoter. CONCLUSION: Our results indicate that the spasmogen specific receptor locus may be a key site of regulation determining the magnitude of spasmogen mediated ASM IPx responses during airway inflammation or following asthma medication. These data provide further insight into the molecular basis of AHR and extend our understanding of potentially detrimental effects associated with existing therapies used in the treatment of asthma.

Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus. Publishing Authors By Initials

N Smith,CA Browning,N Duroudier,C Stewart,S Peel,C Swan,IP Hall,I Sayers,N Smith,CA Browning,N Duroudier,C Stewart,S Peel,C Swan,IP Hall,I Sayers,N Smith,CA Browning,N Duroudier,C Stewart,S Peel,C Swan,IP Hall,I Sayers,N Smith,CA Browning,N Duroudier,C Stewart,S Peel,C Swan,IP Hall,I Sayers,

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Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Respiratory research

VOLUME: 8

Page Numbers: 68

Journal Abbreviation: Respir. Res.

ISSN: 1465-993X

DAY: 28

MONTH: 09

YEAR: 2007

Salmeterol and cytokines modulate inositol-phosphate signalling in human airway smooth muscle cells via regulation at the receptor locus. Information

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LANGUAGE: eng

NlmUniqueID: 101090633

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AFFILIATION: Division of Therapeutics & Molecular Medicine, University Hospital of Nottingham, Nottingham, UK. mzywnas@nottingham.ac.uk

Country: England

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MEDLINETA: Respir Res

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