Our study demonstrates that GdCl
3, a specific inhibitor of Kupffer cell phagocytosis [
4], decreases the rate of LPS-induced TNF-alpha, PGE
2 and NOx production by PCLS; those 3 molecules are known as typical mediators produced by macrophages (and namely by Kupffer cells in culture) upon stimulation by LPS (cytokines, lipid mediators and reactive intermediates) [
10]. Moreover, we have shown that PCLS are able, independently of any stimulus (absence of LPS or any toxic agents) to produce TNF-alpha, NOx and PGE
2. In this case also, the release of mediators is decreased by previous GdCl
3 treatment. Therefore, we conclude that PCLS from GdCl
3-treated rats é compared to PCLS obtained from control rats é is a convenient in vitro system to study the complex Kupffer cell-hepatocyte interactions retained inside the liver tissue, in basal conditions or after an inflammatory stimulus. PGE
2 merits special attention: when PCLS are prepared from Gd+ animals, PGE
2 release is strongly depressed (mainly during short time incubation) suggesting that Kupffer cells are important producers of PGE
2 by the liver. Since GdCl
3 treatment leads to a strong depression of PGE
2 concentration in the serum, we may propose that Kupffer cells inside the liver constitute an important source of circulating PGE
2, known to exert pleiotropic effects outside the liver (control of lipolysis, platelet aggregation, gastric acid secretion, immunoregulation, neurotransmitter release, contraction-relaxation of smooth muscle) [
11]. On the other hand, we show here that PGE
2 release by Kupffer cells, not only plays a role in the systemic availability of this prostaglandin, but is also able to exert paracrine effect on hepatocyte, with relevant metabolic consequences in the liver tissue: we had previously shown that,
in vivo, the accumulation of lipids in the liver tissue after GdCl
3 administration, modifies the histological image of the liver, revealing steatosis [
6]. We have demonstrated in the results presented here that the inhibition of Kupffer cells by GdCl
3 leads to a higher cholesterol, triglycerides and phospholipids synthesis by PCLS, a phenomenon related to a lower PGE
2 release. Since PGE
2 alone added in the culture medium of isolated hepatocytes decreases lipid synthesis, we may postulate that the lower PGE
2 secretion after GdCl
3 treatment is, at least partly, responsible for a higher lipid synthesis inside the liver tissue. This is in favour of a role of Kupffer cell-released PGE
2 in the physiological control of lipid synthesis in hepatocytes. By which mechanism PGE
2 could control lipid synthesis in the liver tissue? The phosphorylation rate of hepatic enzymes involved in the lipogenesis or cholesterogenesis pathways (acetyl-CoA synthetase, HMG-CoA-reductase) could be modulated by PGE
2 which is released at concentration sufficient to alter the phosphorylation of specific proteins inside the hepatocytes [
12]. The use of indomethacin, known to inhibit prostaglandin production, in the incubation medium of PCLS could help to elucidate the role of PGE
2released by Kupffer cell in the regulation of hepatic metabolism.