title: The C allele of rs5743836 polymorphism in the human TLR9 promoter links IL-6 and TLR9 up-regulation and confers increased B-cell proliferation.
abstract: In humans, allelic variants in Toll-like receptors (TLRs) associate with several pathologies. However, the underlying cellular and molecular mechanisms of this association remain largely unknown. Analysis of the human TLR9 promoter revealed that the C allele of the rs5743836 polymorphism generates several regulatory sites, including an IL-6-responding element. Here, we show that, in mononuclear cells carrying the TC genotype of rs5743836, IL-6 up-regulates TLR9 expression, leading to exacerbated cellular responses to CpG, including IL-6 production and B-cell proliferation. Our study uncovers a role for the rs5743836 polymorphism in B-cell biology with implications on TLR9-mediated diseases and on the therapeutic usage of TLR9 agonists/antagonists.
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.
authors: Agostinho
authors: A
authors: Carvalho
authors: Nuno S
authors: NS
authors: Osório
authors: Margarida
authors: M
authors: Saraiva
authors: Cristina
authors: C
authors: Cunha
authors: Agostinho J
authors: AJ
authors: Almeida
authors: Maria
authors: M
authors: Teixeira-Coelho
authors: Paula
authors: P
authors: Ludovico
authors: Jorge
authors: J
authors: Pedrosa
authors: Lucia
authors: L
authors: Pitzurra
authors: Franco
authors: F
authors: Aversa
authors: Luigina
authors: L
authors: Romani
authors: António G
authors: AG
authors: Castro
authors: Fernando
authors: F
authors: Rodrigues
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics*; D008213:Lymphocyte Activation / Q000187:drug effects; D008954:Models, Biological; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*
chemical_list: C408982:CPG-oligonucleotide; D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9