The role of the liver in the response to LPS: experimental and clinical findings.
The liver plays an important physiological role in lipopolysaccharide (LPS) detoxification and, in particular, hepatocytes are involved in the clearance of endotoxin of intestinal derivation. In experimental shock models, tumor necrosis factor (TNF)-alpha induces hepatocyte apoptosis and lethal effects are due to secreted TNF-alpha and not to cell-associated TNF-alpha. An exaggerated production of TNF-alpha has been reported in murine viral infections, in which mice become sensitized to low amounts of LPS and both interferon (IFN)-gamma and IFN-alpha/beta are involved in the macrophage-induced release of TNF-alpha. The prominent role of LPS and TNF-alpha in liver injury is also supported by studies of ethanol-induced hepatic damage. In humans, evidence of LPS-induced hepatic injury has been reported in cirrhosis, autoimmune hepatitis, and primary biliary cirrhosis and a decreased phagocytic activity of the reticulo-endothelial system has been found in these diseases. The origin of endotoxemia in hepatitis C virus (HCV) infected patients seems to be multifactorial and LPS may be of exogenous or endogenous derivation. In endotoxemic HCV-positive patients responsive to a combined treatment with IFN-alpha/ribavirin (RIB), endotoxemia was no longer detected at the end of the therapeutic regimen. By contrast, 48% of the non-responders to this treatment were still endotoxemic and their monocytes displayed higher intracellular TNF-alpha and interleukin (IL)-1beta levels than responders. Moreover, in responders, an equilibrium between IFN-gamma and IL-10 serum levels was attained. In the non-responders, serum levels of IL-10 did not increase following treatment. This may imply that an imbalance between T helper (Th)1 and Th2 derived cytokines could be envisaged in the non-responders.
Jirillo
E
E
Department of Clinical Medicine, Immunology and Infectious Diseases, University of Bari, Bari, Italy. jirillo@midim.uniba.it
Caccavo
D
D
Magrone
T
T
Piccigallo
E
E
Amati
L
L
Lembo
A
A
Kalis
C
C
Gumenscheimer
M
M
D000818:Animals; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D014115:Toxemia / Q000209:etiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D007375:Interleukin-1; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha