Prostaglandin E2 downregulates Kupffer cell production of IL-1 and IL-6 during hepatic regeneration

Abstract

The mammalian liver possesses the ability to regenerate to its original size after a 70% partial hepatectomy (PHx). The capacity of rat Kupffer cells (KC) isolated at specific intervals after PHx to produce interleukin (IL)-1, IL-6, and prostaglandin E2 (PGE2) in response to endotoxin [lipopolysaccharide (LPS)] stimulation was evaluated in standard RPMI 1640 (1,200 microM L-arginine) and arginine-depleted RPMI 1640 (< 10 microM L-arginine) media. Because KC function in an environment in which high arginase activity results in negligible L-arginine levels, the 10 microM L-arginine RPMI 1640 was used to simulate the hepatic microenvironment. Regenerating liver KC 12-120 h after PHx responded to LPS with a significantly greater (P < 0.05) production of IL-1 and IL-6 in standard RPMI 1640. This enhancement of regenerating liver KC to produce IL-1 and IL-6 was increased (P < 0.05) by placing these same KC in 10 microM arginine RPMI 1640 culture media. During the same time period, regenerating liver KC produced significantly elevated (P < 0.01) PGE2, again with greater differences in the low-arginine media. In vivo KC PGE2 blockade by indomethacin (5 mg/kg) significantly (P < 0.05) inhibited hepatic regeneration. When the cyclooxygenase inhibitor indomethacin (10 microM) was added to cultures, the production of PGE2 by KC was prevented, and in arginine-depleted cultures, IL-1 and IL-6 production was upregulated (P < 0.05). We conclude that during hepatic regeneration, KC IL-1 and IL-6 production is elevated and is controlled in an autoregulatory fashion by elevated KC PGE2 production.

Elevated interleukin 6 is induced by prostaglandin E2 in a murine model of inflammation: possible role of cyclooxygenase-2.

“…Most of the confusion comes from trying to compare results obtained with different cell types, from comparing cell lines to primary cells, or from using different agents and conditions to stimulate cytokine and eicosanoid production. Production of IL-6 in a fibroblast cell line (45) and in peritoneal mast cells (46) is stimulated by addition of exogenous prostaglandin, but PGE2 inhibits IL-6 synthesis in resident liver macrophages (Kupfer cells) (47). Similarly, indomethacin inhibits IL-6 production by rat bone marrow macrophages (48) but not human articular chondrocytes (49), or bovine aortic endothelial cells (50).…”

Hemodynamic interaction between portal vien and hepatic artery flow in small-for-size split liver transplantation

“…Flow injury to sinusoidal endothelial cells and activation of Kupffer's cells has been described after extended liver resections in rats [14]. The immunological component of high portal inflow injury is characterized by the release of a number of cytokines, which trigger an inflammatory response to the host, resulting in graft failure [5,171. During the early postoperative period in human liver transplantation, hepatic artery flow is only 10% of the total liver flow [6,9,14] and may be further diminished by the coexistence of warm ischemic injury, acute rejection, and poor arterial reconstruction technique [2,15,161.…”

“…Life-sustaining functions may be jeopardized either by an inadequate quantity of liver parenchyma or by intrahepatic hemodynamic alterations potentially injurious to the graft [6, 14, 151. Experimental and clinical studies have demonstrated that hepatic artery flow is mainly regulated by portal vein flow; increased portal vein flow decreasing hepatic artery flow [5,9,171. We tested the hypothesis that in split-liver transplantation, the relative increase of portal vein flow during the reperfusion period may have a detrimental effect on hepatic arterial flow.…”

Potentiation of Lipopolysaccharide-Induced IL-6 Release by Uridine Triphosphate in Macrophages: Cross-Interaction with Cyclooxygenase-2-Dependent Prostaglandin E₂ Production

“…Although PMA alone cannot stimulate a significant production of IL-6, it synergizes with LPS in the production of IL-6 in murine macrophages [28]. On the contrary, a negative regulation by PKC is suggested in IL-6 synthesis by basic fibroblast growth factor, TNF-·, thrombin and IL-1 in osteoblast-like cells [17][18][19][20][21] and by IL-1 in human monocytes [10]. Thus, it seems that a tissue-and cell-specific role for PKC regulation on IL-6 production exists [3,13,28].…”