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Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis
Author(s) -
Mao Tin Ky,
Lian ZheXiong,
Selmi Carlo,
Ichiki Yasunori,
Ashwood Paul,
Ansari Aftab A.,
Coppel Ross L.,
Shimoda Shinji,
Ishibashi Hiromi,
Gershwin M. Eric
Publication year - 2005
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20859
Subject(s) - tlr5 , immunology , innate immune system , primary biliary cirrhosis , toll like receptor , lipoteichoic acid , pathogen associated molecular pattern , tlr4 , immune system , tumor necrosis factor alpha , acquired immune system , lipopolysaccharide , tlr9 , tlr7 , medicine , biology , pattern recognition receptor , bacteria , genetics , staphylococcus aureus , biochemistry , gene expression , dna methylation , gene
The role of the adaptive immune response, with regard to the development of autoantibodies, has been extensively studied in primary biliary cirrhosis (PBC). However, the importance of innate immunity has been noted only recently. Based on the proposed role of microorganisms in the pathogenesis of the disease, we hypothesize that patients with PBC possess a hyper‐responsive innate immune system to pathogen‐associated stimuli that may facilitate the loss of tolerance. To address this issue, we isolated peripheral blood monocytes from 33 patients with PBC and 26 age‐matched healthy controls and stimulated such cells in vitro with defined ligands for toll‐like receptor (TLR) 2 (lipoteichoic acid; LTA), TLR3 (polyIC), TLR4 (lipopolysaccharide; LPS), TLR5 (flagellin), and TLR9 (CpG‐B). Supernatant fluids from the cultures were analyzed for levels of 5 different pro‐inflammatory cytokines, interleukin (IL)‐1β, IL‐6, IL‐8, IL‐12p70, and TNF‐α. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro‐inflammatory cytokines, particularly IL‐1β, IL‐6, IL‐8, and TNF‐α, compared with controls. In conclusion , monocytes from patients with PBC appear more sensitive to signaling via select TLRs, resulting in secretion of selective pro‐inflammatory cytokines integral to the inflammatory response that may be critical in the breakdown of self‐tolerance. (H EPATOLOGY 2005;42:802–808.)