Altered monocyte responses to defined TLR ligands in patients with primary biliary cirrhosis.
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)-1beta, IL-6, IL-8, IL-12p70, and TNF-alpha. After in vitro challenge with TLR ligands, PBC monocytes produced higher relative levels of pro-inflammatory cytokines, particularly IL-1beta, IL-6, IL-8, and TNF-alpha, 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.
Mao
Tin Ky
TK
Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA 95616, USA.
Lian
Zhe-Xiong
ZX
Selmi
Carlo
C
Ichiki
Yasunori
Y
Ashwood
Paul
P
Ansari
Aftab A
AA
Coppel
Ross L
RL
Shimoda
Shinji
S
Ishibashi
Hiromi
H
Gershwin
M Eric
ME
D000328:Adult; D000368:Aged; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005408:Flagellin / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000378:metabolism / Q000494:pharmacology; D011070:Poly I-C / Q000378:metabolism / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013682:Teichoic Acids / Q000378:metabolism / Q000494:pharmacology; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
C408982:CPG-oligonucleotide; D016207:Cytokines; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; C495346:TLR5 protein, human; C495371:TLR9 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D005408:Flagellin; C009900:lipoteichoic acid; D011070:Poly I-C