Corticosteroids and beta2 agonists differentially regulate rhinovirus-induced interleukin-6 via distinct Cis-acting elements.
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.
Edwards
Michael R
MR
Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, London W2 1PG, United Kingdom. michael.edwards@ic.ac.uk
Haas
Jennifer
J
Panettieri
Rey A
RA
Johnson
Malcolm
M
Johnston
Sebastian L
SL
D000305:Adrenal Cortex Hormones / Q000494:pharmacology / Q000627:therapeutic use; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000730:Androstadienes / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000821:virology; D001980:Bronchi / Q000378:metabolism / Q000473:pathology / Q000821:virology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000821:virology; D000068298:Fluticasone; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010850:Picornaviridae Infections / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000821:virology; D020218:Response Elements; D012229:Rhinovirus / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D000068299:Salmeterol Xinafoate; D014158:Transcription, Genetic / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D000893:Anti-Inflammatory Agents; D022762:CCAAT-Enhancer-Binding Proteins; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D005576:Colforsin; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000242:Cyclic AMP; D020889:Rolipram; D000420:Albuterol