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Peripheral blood mononuclear cell expression of toll‐like receptors and relation to cytokine levels in cirrhosis
Author(s) -
Riordan Stephen M.,
Skinner Narelle,
Nagree Ammar,
McCallum Helen,
McIver Christopher J.,
Kurtovic Jelica,
Hamilton John A.,
Bengmark Stig,
Williams Roger,
Visvanathan Kumar
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2003.50180
Subject(s) - peripheral blood mononuclear cell , cytokine , receptor , immunology , peripheral blood , toll , medicine , peripheral , biology , in vitro , biochemistry
Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor α (TNF‐α) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll‐like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF‐α in response to endotoxin and Gram‐positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF‐α, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF‐α production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF‐α levels, and in vitro TNF‐α production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram‐positive bacteria. Endotoxin, TNF‐α, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up‐regulated in cirrhosis and correlated significantly with serum TNF‐α and sTNFR levels. In vitro TNF‐α production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up‐regulation of PBMC expression of TLR2. Serum TNF‐α levels were further increased and in vitro TNF‐α production further reduced in most patients. In conclusion, up‐regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram‐positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF‐α and sTNFR levels in cirrhosis.