title: Budesonide and formoterol reduce early innate anti-viral immune responses in vitro.
abstract: Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10⁻⁶ M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2', 5' oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined.
authors: Lung and Allergy Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital Clinical Division, Woolloongabba, Queensland, Australia. j.davies2@uq.edu.au
authors: Janet M
authors: JM
authors: Davies
authors: Melanie L
authors: ML
authors: Carroll
authors: Hongzhuo
authors: H
authors: Li
authors: Alisa M
authors: AM
authors: Poh
authors: Darren
authors: D
authors: Kirkegard
authors: Michelle
authors: M
authors: Towers
authors: John W
authors: JW
authors: Upham
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000328:Adult; D000634:Aminoquinolines / Q000494:pharmacology; D001249:Asthma / Q000276:immunology / Q000473:pathology; D001993:Bronchodilator Agents / Q000494:pharmacology; D019819:Budesonide / Q000494:pharmacology*; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004797:Enzyme-Linked Immunosorbent Assay; D004983:Ethanolamines / Q000494:pharmacology*; D005260:Female; D000068759:Formoterol Fumarate; D006801:Humans; D000077271:Imiquimod; D007113:Immunity, Innate / Q000187:drug effects*; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D008297:Male; D008875:Middle Aged; D012229:Rhinovirus / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists
chemical_list: D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D001993:Bronchodilator Agents; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D004983:Ethanolamines; D016898:Interferon-alpha; D015850:Interleukin-6; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D019819:Budesonide; D000077271:Imiquimod; D000068759:Formoterol Fumarate