PRODUCTION OF EICOSANOIDS AND CYTOKINES BY KUPFFER CELLS FROM YOUNG AND OLD RATS STIMULATED BY ENDOTOXIN

1. The clinicopathological features of endotoxaemia have been ascribed to cytotoxic mediators such as tumour necrosis factor, interleukins a nd eicosanoids. Macrophages, particularly Kupffer cells, are an import ant source of these mediators, Mortality from endotoxaemia is highly a ge related. 2. These studies focus on the role of hepatic Kupffer cell s in the increased sensitivity of old rats to bacterial endotoxins. Po ssible age-related changes in the production of eicosanoids and induct ion of gene expression and secretion of interleukin 1, tumour necrosis factor and interleukin 6 were investigated in Kupffer cells derived f rom both young and old animals. 3. Basal production of biological resp onse modifiers was low in cells of both young and old rats, Lipopolysa ccharide stimulated production of the same types of monokines as descr ibed for other types of macrophages, although the pattern was specific for Kupffer cells. 4. Eicosanoids, predominantly prostaglandin D-2 an d prostaglandin F-2 alpha, were produced mainly during the first hour after exposure to lipopolysaccharide, Endotoxin stimulated synthesis o f mRNAs of interleukin 1, interleukin 6 and tumour necrosis factor alp ha resulting in increased secretion of these cytokines into the medium . 5. Kupffer cells from both young and aged animals appear to be exqui sitely sensitive to endotoxin in respect of expression of mRNA for bot h interleukin 1 alpha and interleukin 1 beta and less sensitive with r espect to interleukin 6 and tumour necrosis factor a gene expression, At relatively high lipopolysaccharide concentrations interleukin 6 was secreted in particularly large amounts. 6. The effects of ageing on a ny of these responses of Kupffer cells were minimal 7. It seems unlike ly that age-related changes in the synthesis and secretion of eicosano ids and cytokines by Kupffer cells are an important factor in the incr eased susceptibility of old rats to LPS.