Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alanine Transaminase / blood
-
Animals
-
Cell Line
-
Cells, Cultured
-
Chaperonin 60 / pharmacology*
-
Chaperonin 60 / physiology
-
DNA-Binding Proteins / genetics
-
Female
-
Galactosamine / pharmacology
-
Gene Expression / genetics
-
Interleukin-6 / metabolism
-
Kupffer Cells / drug effects
-
Kupffer Cells / metabolism
-
Kupffer Cells / physiology*
-
Lipopolysaccharides / pharmacology*
-
Liver / drug effects
-
Liver / metabolism
-
Liver Failure / chemically induced
-
Liver Failure / prevention & control
-
Macrophage Activation / drug effects
-
Macrophage Activation / immunology*
-
Macrophage Activation / physiology
-
Male
-
Mice
-
Oligodeoxyribonucleotides / pharmacology*
-
Receptors, Cell Surface / genetics
-
Reverse Transcriptase Polymerase Chain Reaction
-
Toll-Like Receptor 4
-
Toll-Like Receptor 9
-
Tumor Necrosis Factor-alpha / analysis
-
Tumor Necrosis Factor-alpha / metabolism
Substances
-
CPG-oligonucleotide
-
Chaperonin 60
-
DNA-Binding Proteins
-
Interleukin-6
-
Lipopolysaccharides
-
Oligodeoxyribonucleotides
-
Receptors, Cell Surface
-
Tlr4 protein, mouse
-
Tlr9 protein, mouse
-
Toll-Like Receptor 4
-
Toll-Like Receptor 9
-
Tumor Necrosis Factor-alpha
-
Galactosamine
-
Alanine Transaminase