TITLE

TOLL-LIKE RECEPTOR EXPRESSION IN CIRRHOSIS

AUTHOR(S)
Riordan, S.M.; Skinner, N.; Nagree, A.; McCallum, H.; McIver, C.J.; Kurtovic, J.; Hamilton, J.A.; Bengmark, S.; Williams, R.; Visvanathan, K.
PUB. DATE
April 2003
SOURCE
Gut;Apr2003 Supplement 1, Vol. 52, pA1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Background: Pro-inflammatory cytokines such as tumour necrosis factor α (TNFα) contribute to liver damage in cirrhosis. Relevant to this is the expression of toll-like receptor (4) and TLR2, critically involved in TNFα production in response to endotoxin and Gram-positive stimuli, respectively, the first studies on which in cirrhosis are reported here. Methods: We measured in 36 cirrhotic patients and 32 controls (a) circulating endotoxin and TNFα levels; (b) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2; and (c) in vitro production of TNFα by PBMCs in response to stimulation by endotoxin or Staphylococcus aureus enterotoxin B (SEB), a Gram-positive microbial antigen. To determine the role of Gram-positive gut flora, TLR2 expression and TNFα production were re-assessed after supplementation for 7 days with a synbiotic regimen (Synbiotic 2000; Medipharm, Sweden) known to increase intestinal levels of Gram-positive bacteria. Results: Circulating endotoxin and TNFα levels were significantly increased in cirrhotic patients but not correlated. Expression of TLR2, but not TLR4, was significantly up-regulated and correlated significantly with serum TNFα levels. In vitro production of TNFα in response to stimulation with SEB was significantly blunted, in keeping with chronic stimulation by Gram-positive antigens in vivo. Oral supplementation with the synbiotic regimen resulted in further, significant up-regulation of systemic TLR2 expression. Further impairment of TNFα production in response to SEB occurred in most patients. Conclusions: Upregulation of TLR2 but not TLR4 in cirrhosis implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial antigens but not endotoxin. Such Gram-positive antigens may be derived from the gut. Signalling via TLR2 contributes to increased circulating TNF-α levels in cirrhosis.
ACCESSION #
9747253

 

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