title: Regulation of TNF-alpha-induced eotaxin release from cultured human airway smooth muscle cells by beta2-agonists and corticosteroids.
abstract: Eotaxin is a potent eosinophil chemoattractant that contributes to the eosinophilia seen in asthma and other allergic disorders. Recent studies have identified human airway smooth muscle (HASM) as a rich source of eotaxin, but the factors regulating its production are poorly understood. Here we describe for the first time that beta2-agonists can inhibit cytokine-induced eotaxin release. We found that TNF-alpha stimulated eotaxin release (assayed by ELISA) from HASM cells and that the release was partially inhibited by salbutamol and salmeterol. The effect of beta2-agonists was mimicked by forskolin and 8-bromo-cAMP and potentiated by the cAMP-dependent phosphodiesterase inhibitor rolipram, suggesting that it is cAMP dependent. We also found that the cAMP inhibition was likely at the transcription stage, although experiments with the PKA inhibitors H-89 and Rp-cAMP or the PKG inhibitor KT5823 suggested that none of these kinases was involved. Partial inhibition of eotaxin release was also seen with the corticosteroids dexamethasone and fluticasone. The combined use of beta2-agonists, rolipram, and steroids abolished TNF-alpha-induced eotaxin release. These results suggest that the combination of a beta2-agonist, PDE inhibitor, and a corticosteroid may have additive beneficial effects in the treatment of the eosinophilia associated with asthma and other allergic diseases.
authors.affiliation: Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham, UK. mfzlp@unix.ccc.nottingham.ac.uk
authors.forename: L
authors.initials: L
authors.lastname: Pang
authors.forename: A J
authors.initials: AJ
authors.lastname: Knox
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000305:Adrenal Cortex Hormones / Q000494:pharmacology*; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D054413:Chemokine CCL11; D019742:Chemokines, CC; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000068298:Fluticasone; D006801:Humans; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology; D000068299:Salmeterol Xinafoate; D013997:Time Factors; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000305:Adrenal Cortex Hormones; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C026777:ICI 118551; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000068298:Fluticasone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D020889:Rolipram; D000420:Albuterol