title: TLR3 activation increases chemokine expression in human fetal airway smooth muscle cells.
abstract: Viral infections, such as respiratory syncytial virus and rhinovirus, adversely affect neonatal and pediatric populations, resulting in significant lung morbidity, including acute asthma exacerbation. Studies in adults have demonstrated that human airway smooth muscle (ASM) cells modulate inflammation through their ability to secrete inflammatory cytokines and chemokines. The role of ASM in the developing airway during infection remains undefined. In our study, we used human fetal ASM cells as an in vitro model to examine the effect of Toll-like receptor (TLR) agonists on chemokine secretion. We found that fetal ASM express multiple TLRs, including TLR3 and TLR4, which are implicated in the pathogenesis of respiratory syncytial virus and rhinovirus infection. Cells were treated with TLR agonists, polyinosinic-polycytidylic acid [poly(I:C)] (TLR3 agonist), lipopolysaccharide (TLR4 agonist), or R848 (TLR7/8 agonist), and IL-8 and chemokine (C-C motif) ligand 5 (CCL5) secretion were evaluated. Interestingly, poly(I:C), but neither lipopolysaccharide nor R848, increased IL-8 and chemokine (C-C motif) ligand 5 secretion. Examination of signaling pathways suggested that the poly(I:C) effects in fetal ASM involve TLR and ERK signaling, in addition to another major inflammatory pathway, NF-κB. Moreover, there are variations between fetal and adult ASM with respect to poly(I:C) effects on signaling pathways. Pharmacological inhibition suggested that ERK pathways mediate poly(I:C) effects. Overall, our data show that poly(I:C) initiates activation of proinflammatory pathways in developing ASM, which may contribute to immune responses to infection and exacerbation of asthma.
authors.affiliation: Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Mayo Clinic, Rochester, Minnesota;
authors.forename: Arij
authors.initials: A
authors.lastname: Faksh
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota;
authors.forename: Rodney D
authors.initials: RD
authors.lastname: Britt
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Vogel
authors.affiliation: Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Department of Pediatrics, University of Leicester, Leicester, United Kingdom; Department of Immunology, University of Leicester, Leicester, United Kingdom; and.
authors.forename: Hitesh C
authors.initials: HC
authors.lastname: Pandya
authors.affiliation: Department of Pediatrics, Division of Neonatology, Rainbow Babies Children's Hospital, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota;
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota; Department of Anesthesiology, Mayo Clinic, Rochester, Minnesota; Prakash.ys@mayo.edu.
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3
keywords: Toll-like receptor; airway; asthma; chemokine; development; inflammation; virus