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

Background-In patients with alcoholic liver cirrhosis, endotoxaemia is a fr equent finding. Unknown mechanisms, however, prevent typical clinical sympt oms 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 fa ctor (TNF) receptors on phagocytic blood cells in 49 patients with alcoholi c cirrhosis and 41 age matched healthy controls. Results-In addition to increased levels of proinflammatory cytokines in cir rhotic patients, we observed consistent upregulation of the anti-inflammato ry mediators interleukin 10 (IL-10) (plasma 15.75 (1.6) v 6.6 (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) v 331.4 (56) pg/ml (p<0.05); ex vivo 19.9 (3.4) v 10.2 (2.7) ng/ml (p<0.81)), 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 unaltere d 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 respo nse to chronic endotoxaemia. This alteration in immune status may lead to i mpairment of host defences against infections which are frequent complicati ons of alcoholic cirrhosis.