Epistatic effect of TLR-1, -6 and -10 polymorphisms on organic dust-mediated cytokine response

Genes Immun. 2017 Mar;18(2):67-74. doi: 10.1038/gene.2016.51. Epub 2017 Jan 26.

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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged
  • Animal Husbandry
  • Animals
  • Dust*
  • Epistasis, Genetic*
  • Female
  • Humans
  • Immunity, Innate
  • Interleukin-6 / immunology
  • Lipopeptides / immunology
  • Lipopeptides / pharmacology
  • Male
  • Middle Aged
  • Occupational Exposure
  • Peptidoglycan / immunology
  • Polymorphism, Genetic
  • Polymorphism, Single Nucleotide
  • Swine
  • Toll-Like Receptor 1 / genetics*
  • Toll-Like Receptor 1 / immunology
  • Toll-Like Receptor 10 / genetics*
  • Toll-Like Receptor 10 / immunology
  • Toll-Like Receptor 6 / genetics*
  • Toll-Like Receptor 6 / immunology
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Dust
  • IL6 protein, human
  • Interleukin-6
  • Lipopeptides
  • Pam(3)CSK(4) peptide
  • Peptidoglycan
  • TLR10 protein, human
  • TLR6 protein, human
  • Toll-Like Receptor 1
  • Toll-Like Receptor 10
  • Toll-Like Receptor 6
  • Tumor Necrosis Factor-alpha