Volume 3 Supplement 1

11th International Symposium on the Cells of the Hepatic Sinusoid and their Relation to Other Cells

Open Access

The regulatory role of prostaglandin E2in liver (patho) physiology is controlled at its site of synthesis and its action on the receptors

  • Peter Dieter1Email author,
  • Roland Scheibe1,
  • Yefgeniya Bezugla1,
  • Egbert Matthé1,
  • Sandra Schuch1,
  • Lars Treffkorn1,
  • Brigitte Bernard1,
  • Sabine Kamionka1 and
  • Angelika Kolada1
Comparative Hepatology20043(Suppl 1):S35

DOI: 10.1186/1476-5926-2-S1-S35

Published: 14 January 2004

Introduction

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 [1]. 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 [2].

Methods

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 [1].

Results and Discussion

Isolated liver nonparenchymal cells (endothelial cells, Kupffer cells, stellate cells) are characterized by different markers (Table 1).
Table 1

Characterization of endothelial cells (EC), Kupffer cells (KC) and stellate cells (SC) by different markers.

Marker

ED-1

Latex Beads

Ac-LDL

vWF

Reca -1

CD 31

SMA

Desmin

EC

neg

neg + pos

neg + pos

pos

pos

pos

neg

neg

KC

pos

pos

pos

neg

neg

neg

neg

neg

SC

neg

neg

neg

neg

neg

neg

pos

pos

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).
Figure 1

Intracellular free calcium after LPS and platelet activating factor (PAF).

Figure 2

LPS-induced expression of cPLA2, COX-2 and PGE2-synthase (S).

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).
Figure 3

Effect of PGE2 on LPS-induced formation of TNF-alpha, IL-1, ET-1, IL-10 and NO.

Figure 4

Effect of PGE2-receptor agonists (EP -1/-2/-3/-4) on LPS-induced release of ET-1.

PGE2 inhibits proliferation, transdifferentiation and collagen synthesis (Fig. 5) of Stellate cells.
Figure 5

Effect of PGE2 on collagen synthesis (proline incorporation) in stellate cells.

Conclusions

PGE2, produced by Kupffer cells, is a potent physiological suppressor of liver fibrosis (Fig. 6).
Figure 6

PGE2: A potent physiological suppressor of liver fibrosis.

Authors’ Affiliations

(1)
Institute of Physiological Chemistry, Medical Faculty Carl Gustav Carus, TU Dresden

References

  1. 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.Google Scholar
  2. 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.Google Scholar

Copyright

© Dieter et al; licensee BioMed Central Ltd 2004

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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