The effect of adrenaline and Walker-256 tumour-induced cachexia upon Kupffer cell metabolism

Abstract

Kupffer cells (KC), the liver macrophages, are able to produce PGE(2), which is involved in immune suppression and in the aggravation of cancer cachexia due to interference with lipid metabolism in the liver. Since tumour-bearing (TB) rats present high plasma epinephrine levels, and this hormone is able to affect macrophage metabolism and function, we have assessed the effect of epinephrine (5 nM) upon Kupffer cell PGE(2) production. Epinephrine induced increased production of PGE(2) both by control (3.5-fold) and TB rats (27 per cent) KC, an effect blocked by propranolol. Enhancement of cAMP content in the cells by addition of isoproterenol (0.1 microM) to the incubations, however, failed to induce the same response in the cells. Nevertheless, when phenylephrine (1 microM) was added to the incubation, a similar pattern of PGE(2) production to that observed for epinephrine was found for control and TB rat KC. We propose that the effect of epinephrine upon KC PGE(2) production is mediated by alpha-adrenergic receptors and that Ca(2+) is involved in the response, since increasing concentrations of the ion added to the incubation medium (0.25, 0.5 and 1.0 mM) enhanced the eicosanoid production, while EDTA abolished the response.

Cachexia causes time‐dependent activation of the inflammasome in the liver

“…In some diseases, as in cachexia, its metabolism is disrupted, with major consequences to the host's metabolic control and substrate utilization. 6,25 We have also previously described that treatment with indomethacin, decreasing the production of PGE 2 , another relevant inflammatory factor, in cachectic rats, ameliorates metabolic parameters in the organ and partly recovers cachexia-induced wasting. 31 It seems thus clear that the combination of metabolic disruption and inflammation that is systemic in cachexia is also present at the organ/tissue level.…”

“…The liver is a central organ in the management of intermediary metabolism. In some diseases, as in cachexia, its metabolism is disrupted, with major consequences to the host's metabolic control and substrate utilization 6,25 . We have also previously described that treatment with indomethacin, decreasing the production of PGE 2 , another relevant inflammatory factor, in cachectic rats, ameliorates metabolic parameters in the organ and partly recovers cachexia‐induced wasting 31 .…”

“…The gene expression levels of TNF‐α, IL‐1β and IL‐6 are concomitantly increased, and one such inflammatory reaction has been suggested to play a major contribution to hepatic fibrosis and disruption of lipid metabolism 23,24 . A previous study by our group reported that the livers of cachectic rodents suffer impairment of long‐chain fatty acid oxidation, along with disruption of very‐low‐density lipoprotein secretion, leading to steatosis 25 …”

“…23,24 A previous study by our group reported that the livers of cachectic rodents suffer impairment of long-chain fatty acid oxidation, along with disruption of very-low-density lipoprotein secretion, leading to steatosis. 25 Infiltration of immune cells in cachexia does not represent a novel finding as, for instance, the white adipose of both cachectic rodents and cancer patients shows the increased density of inflammatory cells 26,27,28 from which secreted active mediators trigger fibrosis. 26 That may be in fact the reason why when analysed as bulk wet weight, the mass of the adipose depots did not change in the present experiment.…”

Liver denervation affects hepatocyte mitochondrial fatty acid transport capacity

“…Noradrenalin release causes perisinusoidal cells to synthesize prostaglandins 11 and PGF 2 effects on ketogenesis are very similar to those of NA. 12 We have previously shown that Kupffer cells increase their PGE 2 production when incubated with adrenalin, 46 through a calcium-mediated pathway. This was also true for tumour-bearing rat liver, in which CPT II activity is reduced.…”