title: Airway epithelial expression of TLR5 is downregulated in healthy smokers and smokers with chronic obstructive pulmonary disease.
abstract: The TLRs are important components of the respiratory epithelium host innate defense, enabling the airway surface to recognize and respond to a variety of insults in inhaled air. On the basis of the knowledge that smokers are more susceptible to pulmonary infection and that the airway epithelium of smokers with chronic obstructive pulmonary disease (COPD) is characterized by bacterial colonization and acute exacerbation of airway infections, we assessed whether smoking alters expression of TLRs in human small airway epithelium, the primary site of smoking-induced disease. Microarrays were used to survey the TLR family gene expression in small airway (10th to 12th order) epithelium from healthy nonsmokers (n = 60), healthy smokers (n = 73), and smokers with COPD (n = 36). Using the criteria of detection call of present (P call) ≥ 50%, 6 of 10 TLRs (TLRs 1-5 and 8) were expressed. Compared with nonsmokers, the most striking change was for TLR5, which was downregulated in healthy smokers (1.4-fold, p < 10⁻¹⁰) and smokers with COPD (1.6-fold, p < 10⁻¹¹). TaqMan RT-PCR confirmed these observations. Bronchial biopsy immunofluorescence studies showed that TLR5 was expressed mainly on the apical side of the epithelium and was decreased in healthy smokers and smokers with COPD. In vitro, the level of TLR5 downstream genes, IL-6 and IL-8, was highly induced by flagellin in TLR5 high-expressing cells compared with TLR5 low-expressing cells. In the context that TLR5 functions to recognize pathogens and activate innate immune responses, the smoking-induced downregulation of TLR5 may contribute to smoking-related susceptibility to airway infection, at least for flagellated bacteria.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Joumana
authors.initials: J
authors.lastname: Ahmed
authors.forename: Guoqing
authors.initials: G
authors.lastname: Wang
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Hassan
authors.forename: Yael
authors.initials: Y
authors.lastname: Strulovici-Barel
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Salit
authors.forename: Jason G
authors.initials: JG
authors.lastname: Mezey
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000328:Adult; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D005408:Flagellin / Q000009:adverse effects; D016905:Gram-Negative Bacterial Infections / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications / Q000276:immunology* / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D012907:Smoking / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051198:Toll-Like Receptor 5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000502:physiology
chemical_list: C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin