title: Epistatic effect of TLR-1, -6 and -10 polymorphisms on organic dust-mediated cytokine response.
abstract: Exposure to organic dust from agricultural environments is associated with inflammatory respiratory conditions. The putative causal agents in organic dust include viral, microbial and fungal components, which are recognized by the family of Toll-like receptors (TLRs) and drive host innate and adaptive responses. Our aim in this study was to determine whether responsiveness to organic dust among agricultural workers was dependent on polymorphisms in the TLR10-TLR1-TLR6 gene cluster. We stimulated whole blood from 509 agricultural workers with organic dust, triacyl lipopeptide N-palmitoyl-S-dipalmitoylglyceryl Cys-Ser-(Lys)4(Pam3CSK4) and the diacyl-lipopeptide peptidoglycan. Several of the tagging polymorphisms and haplotypes conferred hyper-responsiveness to organic dust with an increase in interleukin-6 (IL-6; P<0.005), but not tumor necrosis factor-α (TNF-α), secretion. We conclude that genetic variation in the TLR10-TLR1-TLR6 gene cluster mediates responsiveness to organic dust, but indicates different signaling pathways for IL-6 and TNF-α. These studies provide new insight into the role of the TLR10-TLR1-TLR6 gene cluster and the innate immune response to organic dust.
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Smith
authors.affiliation: Department of Epidemiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Weissenburger-Moser
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Heires
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Bailey
authors.affiliation: Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.|Veterans Nebraska Western Iowa Healthcare System, Omaha, NE, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Romberger
authors.affiliation: Department of Epidemiology, University of Nebraska Medical Center, Omaha, NE, USA.|Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA.|Veterans Nebraska Western Iowa Healthcare System, Omaha, NE, USA.
authors.forename: T D
authors.initials: TD
authors.lastname: LeVan
mesh_terms: D000368:Aged; D000822:Animal Husbandry; D000818:Animals; D004391:Dust; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000276:immunology; D055666:Lipopeptides / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D010457:Peptidoglycan / Q000276:immunology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013552:Swine; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000276:immunology; D051201:Toll-Like Receptor 10 / Q000235:genetics* / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D004391:Dust; C508600:IL6 protein, human; D015850:Interleukin-6; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D010457:Peptidoglycan; C475955:TLR10 protein, human; C495368:TLR6 protein, human; D051194:Toll-Like Receptor 1; D051201:Toll-Like Receptor 10; D051216:Toll-Like Receptor 6; D014409:Tumor Necrosis Factor-alpha