Abstract
Interleukin-6 (IL-6) is a proinflammatory cytokine up-regulated by rhinovirus infection during acute exacerbations of asthma and chronic obstructive pulmonary disease. The role of IL-6 during exacerbations is unclear; however, it is believed IL-6 could contribute to airway and systemic inflammation. In this study we investigate the effects of common asthma treatments fluticasone propionate and beta(2) agonists salmeterol and salbutamol on IL-6 production in BEAS-2B and primary bronchial epithelial cells. Salmeterol and salbutamol enhanced rhinovirus- and IL-1beta-induced IL-6 production; however, fluticasone treatment caused a reduction of IL-6 protein and mRNA. Combined activity of salmeterol and fluticasone at equimolar concentrations had no effect on rhinovirus or IL-1beta induction of IL-6. The induction of IL-6 by salmeterol was dependent upon the beta(2) receptor and could also be induced by cAMP or cAMP-elevating agents forskolin and rolipram. Using transfection of IL-6 promoter reporter constructs, dominant negative mutants, and electromobility shift assays, it was found that NF-kappaB was the only transcription factor required for rhinovirus induction of IL-6 gene expression. Salmeterol caused an augmentation of rhinovirus-induced promoter activation via a mechanism dependent upon the c/EBP and/or CRE (cyclic AMP response element) cis-acting sites. The suppressive effect of FP was dependent upon distinct glucocorticoid response element sequences proximal to the transcriptional start site within the IL-6 promoter. The data demonstrate that beta(2) agonists can augment IL-6 expression by other stimuli in an additive manner via cyclic AMP and that the negative effect of steroids is mediated by glucocorticoid response elements within the IL-6 promoter.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenal Cortex Hormones / pharmacology
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Adrenal Cortex Hormones / therapeutic use
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Adrenergic beta-Agonists / pharmacology*
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Adrenergic beta-Agonists / therapeutic use
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Albuterol / analogs & derivatives*
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Albuterol / pharmacology*
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Albuterol / therapeutic use
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Androstadienes / pharmacology*
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Androstadienes / therapeutic use
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Anti-Inflammatory Agents / pharmacology*
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Anti-Inflammatory Agents / therapeutic use
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Asthma / complications
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Asthma / drug therapy
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Asthma / metabolism
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Asthma / pathology
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Asthma / virology
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Bronchi / metabolism
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Bronchi / pathology
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Bronchi / virology
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CCAAT-Enhancer-Binding Proteins / metabolism
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Colforsin / pharmacology
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Cyclic AMP / agonists
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Cyclic AMP / metabolism
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Epithelial Cells / metabolism
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Epithelial Cells / pathology
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Epithelial Cells / virology
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Fluticasone
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Gene Expression Regulation / drug effects
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HeLa Cells
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Humans
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Interleukin-1beta / metabolism
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Interleukin-6 / biosynthesis*
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NF-kappa B / metabolism
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Phosphodiesterase Inhibitors / pharmacology
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Picornaviridae Infections / drug therapy
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Picornaviridae Infections / etiology
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Picornaviridae Infections / metabolism*
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Pulmonary Disease, Chronic Obstructive / complications
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Pulmonary Disease, Chronic Obstructive / drug therapy
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Pulmonary Disease, Chronic Obstructive / metabolism
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Pulmonary Disease, Chronic Obstructive / pathology
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Pulmonary Disease, Chronic Obstructive / virology
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Response Elements*
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Rhinovirus* / metabolism
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Rolipram / pharmacology
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Salmeterol Xinafoate
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Transcription, Genetic / drug effects
Substances
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Adrenal Cortex Hormones
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Adrenergic beta-Agonists
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Androstadienes
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Anti-Inflammatory Agents
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CCAAT-Enhancer-Binding Proteins
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IL6 protein, human
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Interleukin-1beta
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Interleukin-6
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NF-kappa B
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Phosphodiesterase Inhibitors
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Colforsin
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Salmeterol Xinafoate
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Fluticasone
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Cyclic AMP
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Rolipram
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Albuterol