Among the hormone class of the eicosanoids, PGE2 plays a predominant role in liver (patho) physiology. Liver-specific responses, like regulation of blood glucose homeostasis, sinusoidal blood flow within the liver, properties of the transendothelial barrier within the liver, synthesis and release of important other mediators like cytokines, growth factors or nitric oxide, and liver fibrogenesis have been shown to be mediated or regulated by PGE2 . Within the liver, the main producers of PGE2 are the Kupffer cells. The synthesis of PGE2 in Kupffer cells is controlled at multiple levels. The action of PGE2 on its target cells is mediated by 4 classes of PGE2 receptors (EP1, EP2, EP3, EP4). Each of these receptors converts the information of PGE2 by different intracellular signal pathways to a specific cellular response .
Liver nonparenchymal cells (endothelial cells, Kupffer cells, stellate cells) are isolated from male rat livers by a pronase/collagenase perfusion. Experiments are performed with cells kept in primary cultures .
Results and Discussion
Isolated liver nonparenchymal cells (endothelial cells, Kupffer cells, stellate cells) are characterized by different markers (Table 1).
The fast synthesis of PGE2 in Kupffer cells (induced by, e.g., platelet activating factor, zymosan, calcium ionophore) requires a sustained increase of cellular calcium (Fig. 1). The delayed synthesis of PGE2 in Kupffer cells (induced by, e.g., LPS) is paralleled by a transient increase of cellular calcium (Fig. 1), and requires a de novo / enhanced expression of cytosolic phospholipase A2 (cPLA2), cyclooxygenase (COX)- 2 and PGE2 synthase (Fig. 2).
Besides eicosanoids, LPS induces in Kupffer cells the release of other mediators, including IL-1, IL-10, TNF-alpha, ET-1, and NO (1). The release of IL-1, TNF-alpha and ET-1 is totally suppressed by PGE2, the release of IL-10 and NO (1) is enhanced by PGE2 (Fig. 3). The regulation of the synthesis of IL-1, IL-10, TNF-alpha (Fig. 4) and ET-1 in Kupffer cells by PGE2 is mediated by EP-2 and EP-4, as demonstrated by the use of PGE2-receptor-specific agonists (EP-1/-2/-3/-4:ONO-DI-004/-AE1-259/-AE-248/-AE1-329).
PGE2 inhibits proliferation, transdifferentiation and collagen synthesis (Fig. 5) of Stellate cells.
PGE2, produced by Kupffer cells, is a potent physiological suppressor of liver fibrosis (Fig. 6).
Dieter P, Scheibe R, Télzer S, Kamionka S, Kolada A: Prostaglandin E2, an important regulator in (patho) physiological liver functions. In: Cells of the Hepatic Sinusoid. Edited by: Wisse E, Knook DL, de Zanger R, Arthur MJP. 1999, Leiden, Kupffer Cell Foundation, 8: 6-10.
Fennekohl A, Segi E, Sugimoto Y, Ichikawa A, Péschel GP: Parallel action of EP2 and EP4 receptor for the prostaglandin E2-mediated feedback inhibition of the LPS-induced TNF-alpha formation in mouse Kupffer cells. In: Cells of the Hepatic Sinusoid. Edited by: Wisse E, Knook DL, de Zanger R, Arthur MJP. 2001, Leiden, Kupffer Cell Foundation, 8: 11-14.
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Dieter, P., Scheibe, R., Bezugla, Y. et al. The regulatory role of prostaglandin E2in liver (patho) physiology is controlled at its site of synthesis and its action on the receptors. Comp Hepatol 3, S35 (2004). https://doi.org/10.1186/1476-5926-2-S1-S35
- Nitric Oxide
- Liver Fibrosis
- Kupffer Cell
- Stellate Cell