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 and eicosanoids. Macrophages, particularly Kupffer cells, are an important source of these mediators, Mortality from endotoxaemia is highly age related. 2. These studies focus on the role of hepatic Kupffer cells in the increased sensitivity of old rats to bacterial endotoxins. Possible age-related changes in the production of eicosanoids and induction of gene expression and secretion of interleukin 1, tumour necrosis factor and interleukin 6 were investigated in Kupffer cells derived from both young and old animals. 3. Basal production of biological response modifiers was low in cells of both young and old rats, Lipopolysaccharide stimulated production of the same types of monokines as described for other types of macrophages, although the pattern was specific for Kupffer cells. 4. Eicosanoids, predominantly prostaglandin D-2 and prostaglandin F-2 alpha, were produced mainly during the first hour after exposure to lipopolysaccharide, Endotoxin stimulated synthesis of mRNAs of interleukin 1, interleukin 6 and tumour necrosis factor alpha resulting in increased secretion of these cytokines into the medium. 5. Kupffer cells from both young and aged animals appear to be exquisitely sensitive to endotoxin in respect of expression of mRNA for both interleukin 1 alpha and interleukin 1 beta and less sensitive with respect 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 any of these responses of Kupffer cells were minimal 7. It seems unlikely that age-related changes in the synthesis and secretion of eicosanoids and cytokines by Kupffer cells are an important factor in the increased susceptibility of old rats to LPS.