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


CONCLUSIONS
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.
Schuchmann
Marcus
M
Department of Medicine, University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany. schuchm@mail.uni-mainz.de
Hermann
Frank
F
Herkel
Johannes
J
van der Zee
Ruurd
R
Galle
Peter R
PR
Lohse
Ansgar W
AW
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000494:pharmacology* / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005688:Galactosamine / Q000494:pharmacology; D015870:Gene Expression / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D017093:Liver Failure / Q000139:chemically induced / Q000517:prevention & control; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D008297:Male; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
C408982:CPG-oligonucleotide; D018834:Chaperonin 60; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine; D000410:Alanine Transaminase