The C allele of rs5743836 polymorphism in the human TLR9 promoter links IL-6 and TLR9 up-regulation and confers increased B-cell proliferation

• Published in: PloS one Vol. 6; no. 11; p. e28256
• Main Authors: Carvalho, Agostinho, Osório, Nuno S, Saraiva, Margarida, Cunha, Cristina, Almeida, Agostinho J, Teixeira-Coelho, Maria, Ludovico, Paula, Pedrosa, Jorge, Pitzurra, Lucia, Aversa, Franco, Romani, Luigina, Castro, António G, Rodrigues, Fernando
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.11.2011; Public Library of Science (PLoS)
• Subjects: Alleles; Analysis; Asthma; B cells; B-Lymphocytes - cytology; B-Lymphocytes - drug effects; Base Sequence; Binding sites; Biology; Cancer; Cell growth; Cell proliferation; Cell Proliferation - drug effects; Cellular manufacture; CpG islands; Crohns disease; Cytokines; Dendritic cells; Deoxyribonucleic acid; Deregulation; DNA; Gene polymorphism; Genes; Genetic aspects; Genotype; Haplotypes; Health aspects; Health sciences; Helicobacter pylori; Humans; Immune system; Interleukin 6; Interleukin-6 - genetics; Laboratories; Leukocytes (mononuclear); Lymphocyte Activation - drug effects; Lymphocytes B; Lymphoma; Lymphomas; Medicine; Minority & ethnic groups; Models, Biological; Molecular modelling; Molecular Sequence Data; Oligodeoxyribonucleotides - pharmacology; Peptides; Polymorphism; Polymorphism, Single Nucleotide - genetics; Promoter Regions, Genetic - genetics; Proteins; Receptors; TLR9 protein; Toll-Like Receptor 9 - genetics; Toll-like receptors; Transcription factors; Transcription, Genetic - drug effects; Up-Regulation - drug effects; Up-Regulation - genetics; Portugal
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028256

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.