The in vivo effect of hepatotrophic factors augmenter of liver regeneration, hepatocyte growth factor, and insulin-like growth factor-II on liver natural killer cell functions

Abstract

Fine balanced sequential changes of the levels of circulating hepatotrophic factors are essential for normal liver regeneration. Our recent studies have indicated that liver-resident natural killer (NK) cells are important regulators of liver regeneration and have raised the possibility that hepatotrophic factors might mediate their activities through NK cells. In the present study, we assessed the effects of in vivo administration of three hepatotrophic factors (augmenter of liver regeneration [ALR], insulin-like growth factor-II [IGF-II], and hepatocyte growth factor [HGF]) on NK cells in normal rats. Each of the three, given over a 1-day period in doses known to produce hepatotrophic activity, induced inhibition of NK cell cytotoxic activities in the population of mononuclear leukocytes (MNL) in the liver, but not in MNL from the spleen or peripheral blood. In contrast to these results obtained by the whole animal treatment, the three molecules had no effect on NK cell functions when added to cultures of MNL from the livers, spleens, or blood of untreated rats. These data support and extend our previously advanced hypothesis that ALR and other hepatotrophic factors play an important role in liver regeneration by regional regulation of NK cells through some as-yet-unknown intermediary mechanism.Hepatotrophic factors (Table 1) have been so characterized [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] by virtue of their ability to augment the hyperproliferative response induced by partial hepatectomy (PH) in rats 3,6 or dogs, 5 and to prevent the atrophy as well as augment the heightened cell renewal caused by portacaval shunt (Eck's fistula) in dogs. 2,4 Only two of the eight known hepatotrophic factors (hepatocyte growth factor [HGF] and transforming growth factor [TGF]-α) are primary mitogens capable of stimulating de novo hepatocyte proliferation in vitro without the requisite precondition of preexisting commitment to heightened cell renewal. Molecules with opposite effects have been called "antihepatotrophic." [16][17][18] After PH, there is an acute temporary increase in the circulating levels of several of the endogenous hepatotrophic factors 1,2,4,5,19 and multiple gene expression in the liver. 20 have speculated that the hepatocyte stimulatory activity of augmenter of liver regeneration (ALR) and the other hepatotrophic factors may be mediated through or by nonparenchymal cells. 1,9,21 This possibility was reinforced by the observation during the acute phase of regeneration after PH in rats of temporary suppression of natural killer (NK) cell functions of liver mononuclear leukocytes (MNL), followed by their recovery at the termination of regeneration. 21 These changes occurred contemporaneously with mirror-image susceptibility of the regenerating hepatocytes to NK-induced lysis.To test this immunologic hypothesis, we have determined in the present study whether the changes of NK cell function occurring after PH could be reproduced in unoperated naive rats by their treatment with three pot...

Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice

“…An insightful finding is the modification of IL-10/ IFN-␥ gene transcription in LDC during the early phase of liver regeneration, and the ability of these cells to induce a similar cytokine pattern when co-cultured with naïve T cells. Notably, a decrease in IFN-␥ has already been demonstrated in the liver tissue and is associated with inhibition of hepatic NK cell lytic activity, 10 -a "physiological" event in the process of hepatocyte proliferation after PH. Furthermore, the concomitant increase in expression of IL-10, a well-known anti-inflammatory cytokine, suggests that LDC may be actively involved in promoting a state of local immune suppression.…”

“…[1][2][3] Although various genetic and biological factors that play a role in this phenomenon have been extensively investigated, [4][5][6][7][8] the mechanisms responsible for the initiation, maintenance, and suspension of hepatocyte proliferation have not been fully elucidated. Two aspects of liver regeneration that appear to be important are (1) strong inhibition of the cytotoxic activity of liver-resident natural killer (NK) cells, which becomes evident within a few hours after partial hepatectomy (PH) and terminates at the end of the regenerative process 9,10 ; and (2) a significant increase in circulating estrogen level and expression of estrogen receptors in tissue, regardless of gender or species. Partial hepatectomy in male animals is followed by an almost complete disappearance of serum androgens and their related tissue receptors in a process known as "feminization" of the male regenerating liver.…”

Augmenter of liver regeneration: An important intracellular survival factor for hepatocytes

“…The mitogenic and antiatrophic activities of native and cloned ALR were demonstrated in partially hepatectomized rats [1] and in dogs with portacaval shunt [2][3][4]6,7]. ALR also inhibits the lytic activity of hepatic natural killer cells [8,9], which is critical for unabated liver regeneration [10]. Presence of hepatotrophic activity in weanling and regenerating [1][2][3]11] but not in the unmodified adult animal livers [1,3] suggested that ALR is not synthesized by the latter.…”

Advances in gene therapy of liver cirrhosis: a review

“…Results showed that NK cell cytotoxic activities were inhibited in the population of mononuclear leukocytes (MNL) in the liver (liver-resident NK cells ), but not in the MNL from the spleen or peripleral blood. Results obtained in vitro displayed that ALR, IGF-II and HGF had no effect on NK cell function in cultured MNL from the liver, spleen or blood [69] . Results from Polimeno et alalso verified that ALR plays a pivotal role as growth factor and as immunoregulator by controlling the mitochondrial transcription factor A expression and lytic activity of liver-resident NK cells through IFN-γ levels [70] and regulates hepatocyte proliferation through enhancing cytochrome content and oxidative phosphorylation capacity of liver-derived mitochondia [71] .…”

“…Liverderived NK cells are important regulators for liver regeneration [68] . Francavilla et al [69] connected the regulation activity of ALR in liver regeneration with the novel role of NK cells. Francavilla et al administrated three hepatotrophic factors (ALR, insulinlike growth factor II [IGF-II] and HGF) with the surely inducing sound hepatotrophic activities to assess the in vivo effects on NK cells in normal rats.…”