Interdependence of tumor necrosis factor, prostaglandin E₂, and protein synthesis in lipopolysaccharide‐exposed rat Kupffer cells

Abstract

Kupffer cells are the main producers of tumor necrosis factor‐α (TNF; cachectin) and eicosanoids in the liver exposed to lipopolysaccharide (endotoxin; LPS). A very rapid but transient release of TNF is followed by a slow, steady synthesis of prostaglandin E2 (PGE2). TNF itself is able to provoke eicosanoid synthesis in Kupffer cells; the rate and pattern of prostaglandin production are similar to those observed after treatment with LPS. Anti‐TNF antibodies completely neutralize TNF action on Kupffer cells, thus ruling out any participation of contaminating LPS. LPS stimulation of PGE2 production in Kupffer cells is reduced by the antiserum to 50%, indicating an involvement of TNF in the stimulatory action of LPS. On the other hand, PGE2, a potent inhibitor of LPS‐elicited TNF release, is able to suppress LPS‐ but not TNF‐stimulated eicosanoid synthesis in rat Kupffer cells. In addition to this autocrine circuit, extrahepatic factors participate in the regulation of Kupffer cell activation: glucocorticoids not only inhibit TNF or prostaglandin production, they also reverse the LPS‐specific changes in the prostaglandin pattern of Kupffer cells. LPS, TNF or cycloheximide when given alone in the concentration range applied in this study do not affect the viability of rat Kupffer cells. However, the combinations of cycloheximide and either LPS or TNF cause rapid death of the cultured cells. The cytolytic potential of either combination cannot be alleviated by treatment with glucocorticoids.

Modulation of phagocytosis by anisoosmolarity and betaine in rat liver macrophages (Kupffer cells) and RAW 264.7 mouse macrophages

“…Upon stimulation with endotoxin these cells produce a variety of cytokines, lipid mediators and radicals. Recent studies have indicated that endotoxin enhances the expression of inducible cyclooxygenase-2 (Cox-2) [2][3][4][5][6], which results in the increased formation of prostanoids by Kupffer cells and other macrophages [3,[7][8][9]. Interestingly, lipopolysaccharide (LPS)-induced prostaglandin E2, D2 and thromboxane B2 formation and Cox-2 expression are stimulated up to 10-fold when ambient osmolarity increases from 300 to 350 mosmol/1 [3].…”

Modulation of tumor necrosis factor‐α release by anisoosmolarity and betaine in rat liver macrophages (Kupffer cells)

“…Upon stimulation with endotoxin these cells produce a variety of cytokines, lipid mediators and radicals. Recent studies have indicated that endotoxin enhances the expression of inducible cyclooxygenase-2 (Cox-2) [2~5], which results in an increased formation of prostanoids by Kupffer cells and other macrophages [3,[7][8][9]. This response to LPS is markedly enhanced in hyperosmotic environments due to an about 10-fold stimulation of *Corresponding author.…”

Induction by interleukin 6 of Gs-coupled prostaglandin E2 receptors in rat hepatocytes mediating a prostaglandin E2–dependent inhibition of the hepatocyte's acute phase response

“…20 The anti-inflammatory action of PGE 2 on Kupffer cells is mediated via G s -coupled PGE 2 receptors and an increase in intracellular cyclic adenosine monophosphate (cAMP). 17 Kupffer cells have been shown to express both G s -coupled PGE 2 receptors, the EP2-R and the EP4-R. 20 In addition to its anti-inflammatory action on Kupffer cells, PGE 2 has been shown to decrease the cytokine-stimulated de novo synthesis of acute phase proteins in rat hepatocytes. 21 It would seem logical, that such an anti-inflammatory action of PGE 2 on hepatocytes should also be mediated by G s -coupled PGE 2 receptors.…”