Endotoxin is physiologically present in portal venous blood at concentratio
ns 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 effic
ient APCs, Here, we studied the influence of endotoxin on the accessory fun
ction of LSEC, Incubation of Ag-presenting LSEC with physiological concentr
ations of endotoxin lead to greater than or equal to 80% reduction of the a
ccessory function, measured by release of IFN-gamma from CD4(+) T cells. In
contrast, conventional APC populations rather showed an increase of the ac
cessory function after endotoxin treatment. Inhibition of the accessory fun
ction in LSEC by endotoxin was not due to lack of soluble costimulatory sig
nals, because neither supplemental IL-1 beta, IL-2, IFN-gamma, or IL-12 cou
ld rescue the accessory function, Ag uptake was not influenced by endotoxin
in LSEC, However, we found that endotoxin led to alkalinization of the end
osomal/lysomal compartment specifically in LSEC but not in bone marrow macr
ophages, which indicated that Ag processing, i.e., proteolytic cleavage of
protein Ags into peptide fragments, was affected by endotoxin, Furthermore,
endotoxin treatment downregulated surface expression of constitutively exp
ressed MHC class II, CD80, and CD86. In conclusion, it is conceivable that
endotoxin does not alter the clearance function of LSEC to remove gut-deriv
ed Ags from portal blood but specifically affects Ag processing and express
ion of the accessory molecules in these cells, Consequently, Ag-specific im
mune responses by CD4(+) T cells are efficiently down-regulated in the hepa
tic microenvironment.