HSP60 and CpG-DNA-oligonucleotides differentially regulate LPS-tolerance of hepatic Kupffer cells

Background/aims: Hepatic Kupffer cells (KC) are major regulators of the immune response to gut-derived bacterial products; uncontrolled activation of KC by bacterial components is of pathogenic relevance in alcoholic hepatitis and septic shock. Methods: We examined the role of bacterial lipopolysaccharide (LPS), bacterial and autologous HSP60 and bacterial DNA, which are recognized by innate Toll-like receptors, during activation of murine KC. Results: In cultivated KC, autologous HSP60 induced a state of LPS-hyporesponsiveness; bacterial DNA did not mitigate the response to subsequent LPS-challenge in vitro; in contrast, pre-treatment of mice with bacterial DNA even significantly increased serum TNF levels, liver function tests and mortality in a model of LPS-induced hemorrhagic liver failure. Conclusion: HSP60 and CpG-DNA differentially modulated the threshold of KC activation by LPS and might therefore contribute to the regulation of inflammatory immunity to gut-derived bacterial compounds. (C) 2004 Elsevier B.V. All rights reserved.