REGULATION OF CD95 (APO-1 FAS) RECEPTOR AND LIGAND EXPRESSION BY LIPOPOLYSACCHARIDE AND DEXAMETHASONE IN PARENCHYMAL AND NONPARENCHYMAL RAT-LIVER CELLS/

The effect of lipopolysaccharide (LPS) on the expression of CD95 (APO- 1/Fas) receptor and ligand (CD95L) was studied in primary cultures of rat liver Kupffer cells (KCs), sinusoidal endothelial cells (SECs), an d parenchymal cells (PCs) at the messenger RNA (mRNA) level and by mea ns of immunocytochemistry. LPS treatment of KCs and SECs led to a thre e-to five-fold increase in CD95L mRNA levels within 6 hours, which dec lined thereafter, Within 24 hours, the number of KCs and SECs staining positive for CD95L strongly increased, After a lag phase of 12 hours after LPS addition, in both cell types the mRNA levels for the soluble CD95 isoform increased approximately 10-fold; however, the number of KCs and SECs staining positive for transmembrane CD95 remained low and did not significantly increase. Compared with nonparenchymal cells, C D95L mRNA levels in primary hepatocyte cultures were low in the absenc e and presence of LPS. On the other hand, functionally active CD95 exp ression markedly increased in response to LPS in these cells. Dexameth asone diminished the LPS-induced stimulation of CD95L expression in no nparenchymal cells but markedly stimulated CD95L expression in PCs. Ap optosis of PCs and thymic lymphocytes was stimulated by the addition o f supernatants derived from LPS-treated KC or SEC cultures and was app arently mediated by CD95L as assessed by its sensitivity to inhibitors of the CD95-dependent apoptotic pathway in PCs. The data suggest a co mplex and timely coordinated interplay between the various liver cell populations with respect to LPS-induced activation of the apoptotic ma chinery with potential relevance for immunoregulation.