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Mechanisms of endotoxin tolerance in patients with alcoholic liver cirrhosis: role of interleukin 10, interleukin 1 receptor antagonist, and soluble tumour necrosis factor receptors as well as effector cell desensitisation

Abstract

BACKGROUND In patients with alcoholic liver cirrhosis, endotoxaemia is a frequent finding. Unknown mechanisms, however, prevent typical clinical symptoms of endotoxaemia in many patients.

METHODS We determined plasma levels of pro- and anti-inflammatory mediators, ex vivo cytokine secretion capacity, and expression of tumour necrosis factor (TNF) receptors on phagocytic blood cells in 49 patients with alcoholic cirrhosis and 41 age matched healthy controls.

RESULTS In addition to increased levels of proinflammatory cytokines in cirrhotic patients, we observed consistent upregulation of the anti-inflammatory mediators interleukin 10 (IL-10) (plasma 15.75 (1.6) v6.6 (1.3) pg/ml (p<0.001); ex-vivo 108.4 (22.0)v 40.1 (7.4) pg/ml (p<0.05)), interleukin 1 receptor antagonist (plasma 527.1 (83) v331.4 (56) pg/ml (p<0.05); ex vivo 19.9 (3.4)v 10.2 (2.7) ng/ml (p<0.01)), and soluble TNF receptors (sTNF-R) in plasma (sTNF-RI 3157.2 (506.2)v 607.9 (300.3) pg/ml; sTNF-RII 3331.0 (506.2) v 1066.4 (225.1) pg/ml (p<0.001 for both)). Desensitisation at the target cell level was indicated by reduced expression of TNF receptor I on granulocytes (64.8 (6.5)v 40.1 (7.3)% positive cells; p<0.05) and unaltered plasma levels of soluble E-selectin.

CONCLUSION In patients with alcoholic liver cirrhosis, upregulation of the pro- and anti-inflammatory cytokine system and simultaneous desensitisation of effector cells could explain the restricted systemic inflammatory response to chronic endotoxaemia. This alteration in immune status may lead to impairment of host defences against infections which are frequent complications of alcoholic cirrhosis.

  • liver cirrhosis
  • lipopolysaccharide
  • lipopolysaccharide desensitisation
  • anti-inflammatory cytokines
  • tumour necrosis factor
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Footnotes

  • Abbreviations used in this paper:
    IL
    interleukin
    IL-1ra
    IL-1 receptor antagonist
    LPS
    lipopolysaccharide
    TNF
    tumour necrosis factor
    sTNF-R
    soluble TNF receptor
    sE-selectin
    soluble E-selectin
    SIRS
    systemic inflammatory response syndrome
    AST
    aspartate aminotransferase
    ALT
    alanine aminotransferase
    GGT
    gamma glutamyltransferase
    PBS
    phosphate buffered saline
    IFN-γ
    interferon γ

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