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*
First Medizinische Klinik und Poliklinik, Johannes Gutenberg Universität, Mainz, Germany;
Zentrum f. Molekulare Biologie, Ruprecht Karls Universität, Heidelberg, Germany; and
Institut für Immunologie, Johannes Gutenberg Universität, Mainz, Germany
Endotoxin is physiologically present in portal venous blood at
concentrations of 100 pg/ml to 1 ng/ml. Clearance of endotoxin from
portal blood occurs through sinusoidal lining cells, i.e., Kupffer
cells, and liver sinusoidal endothelial cells (LSEC). We have recently
shown that LSEC are fully efficient APCs. Here, we studied the
influence of endotoxin on the accessory function of LSEC. Incubation of
Ag-presenting LSEC with physiological concentrations of endotoxin lead
to 
80% reduction of the accessory function, measured by release of
IFN-
from CD4+ T cells. In contrast, conventional APC
populations rather showed an increase of the accessory function after
endotoxin treatment. Inhibition of the accessory function in LSEC by
endotoxin was not due to lack of soluble costimulatory signals, because
neither supplemental IL-1ß, IL-2, IFN-, or IL-12 could rescue the
accessory function. Ag uptake was not influenced by endotoxin in LSEC.
However, we found that endotoxin led to alkalinization of the
endosomal/lysomal compartment specifically in LSEC but not in bone
marrow macrophages, which indicated that Ag processing, i.e.,
proteolytic cleavage of protein Ags into peptide fragments, was
affected by endotoxin. Furthermore, endotoxin treatment down-regulated
surface expression of constitutively expressed MHC class II, CD80, and
CD86. In conclusion, it is conceivable that endotoxin does not alter
the clearance function of LSEC to remove gut-derived Ags from portal
blood but specifically affects Ag processing and expression of the
accessory molecules in these cells. Consequently, Ag-specific immune
responses by CD4+ T cells are efficiently down-regulated in
the hepatic microenvironment.
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