Levels of rna for TNF-α and receptors during the prereplicative period of liver regeneration

Abstract

During the prereplicative period of liver regeneration the changes of the mRNA con-• tents for tumor necrosis factor-a (TNF-a) and its receptors were examined in total liver RNA with the help of reverse transcriptase-polymerase chain reaction (RT-PCR) and compared with those after sham operation or stimulation with Upopolysaccharide (LPS). In regenerating liver all the changes are nearly synchronous with a slight delay for the TNF receptor RNAs. The mRNA levels reach their maximum at 1-3 h after ope ration and exceed the values for intact animals about tenfold. The corresponding chan ges induced by sham operation are quantitatively less than those in the regenerating liver and manifest themselves at the end of the prereplicative period. LPS stimulation induced an increase of TNF-a and TNF receptor production comparable with during re generation. Analysis of the expression of the 55 kDa TNF receptor revealed qualitative changes, e. g. an increased polyadenylation and an imbalance between the amplification of the whole molecule and its 5'-terminal half pointing to as yet unidentified changes at the 3' end of the molecule. Introduction. Liver regeneration following severe injury is an integral process of secondary organ development in which all types of liver cells participate. Although may features of this reparation resemble processes typical for growth and development of neonatal liver, a number of dif ferences are conspicuous. The most prominent is the loss of the previous adult phenotype with the concomitant adaptative and compensatory reac tions; furthermore, responses to stress and local injury differ from the physiological processes of organized proliferation. The main changes triggering the entrance of the injured liver into the cell cycle occur early, during the first 3-4 h after partial hepatectomy. This phase is conside red as the only one preceding the cell cycle and has been named «com petence» [1] in accordance with a similar state of mitotically induced fib roblasts [2]. A similar metabolic reorientation follows the first bioche mical adaptation reactions called «situation check up» [3-5]. A question less often addressed in research on liver regeneration is the particular role of the non-parenchymal cells. They not only partici pate in the growth processes by increasing their number, but must also be seen as contributors of signals and mediators of the whole regenera ting organ. Among the sinus-lining cells of the liver, the resident macro phages, the Kupffer cells, have been found to be the major producers of stress-related factors that influence the metabolic performance of neigh bouring cells [6]. The tumor necrosis factor-a is one of the most potent signal molecules produced by stimulated Kupffer cells that triggers in flammatory and other stress responses in the body [7, 8] and in parti cular after liver injury [9]. Growth factors and cytokines including TNF-a are generally produ ced by non-parenchymal, a. g. mesenchymal cells. They regulate epithe lial cell functions during development and to a...

The Response of Liver Macrophages to Inflammatory Stimulation.

“…LPS stimulation induces an increase in TNF-a and TNF receptor pro duction comparable to that during regeneration. 18 NO production in the regenerating liver,19 as deter mined by electron paramagnetic resonance spectros copy, starts to increase approximately 1h after partial hepatectomy (PHE). A second and more pronounced NO production peak occurs about 6 h after PHE when the hepatocytes enter the first cell cycle.…”

The potential targets of Kupffer cells activity during liver regeneration

“…During the delayed-early response, the action of potent cytokines, e. g. TNF-a and IL-1 [17][18][19][20], and the increased responsiveness to them due to elevated expression of TNF receptors [17] may define the whole set of observed events, e. g. up-regulation of c-fos-and c-myc-and down-regulation of P450IIE1 expression, as demonstrated here, NO production in hepatocytes as shown previously [21,22], proin flammatory and hepatocyte-specific promitogenic re actions, and autostimulation of PGE 2 synthesis [23,24 ]. Prostaglandin E 2 is instrumental in the re gulation of cytokine production [23 ], the increase of intracellulr cAMP [23 ], in relaxation of sinusoids and consequently enhanced blood flow in the liver [25].…”