An injection of D-galactosamine (GalN) into mice together with a lipopolysaccharide (LPS or endotoxin), interleukin-1 (IL-1) or tumour necrosis factor (TNF), sensitized the mice and induced fulminant hepatitis with severe congestion resulting in rapid death. Since LPS and these cytokines induce ornithine decarboxylase (ODC) and histidine decarboxylase (HDC) in the liver and spleen of mice, the effects of GalN on the induction of ODC and HDC in these organs were examined. 2. The induction of ODC by LPS, IL-1 or TNF was suppressed by GalN in the liver, and this suppression preceded the hepatic congestion. There was good agreement between the degree of hepatic congestion and the suppression of ODC induction by various amounts of GalN. The induction of ODC in the spleen was suppressed only at the highest dose of GalN examined. 3. GalN is known to deplete uridine 5'-triphosphate (UTP), resulting in the suppression of RNA and protein synthesis. An injection of uridine, the precursor of UTP, diminished the GalN-induced suppression of ODC induction by LPS and prevented the hepatic congestion and death. 4. LPS-pretreatment before injection of LPS plus GalN prevented the suppression of ODC activity and prevented the hepatic congestion and death. 5. An injection of putrescine, the product of ODC, prolonged survival time and delayed the development of hepatic congestion. However, injection of an ODC inhibitor into the mice given LPS did not produce hepatic congestion. 6. The induction of HDC in the liver by LPS, IL-1 or TNF was not suppressed by GalN and, at high doses, the response to LPS was enhanced. An inhibitor of HDC neither prevented the hepatic congestion nor enhanced the protective effect of putrescine.7. Although GalN in combination with IL-la induced a markedly higher HDC activity than was observed when it was combined with TNFa, and suppressed the induction of ODC, the former combination at the doses used did not produce hepatic congestion or death. However, the sensitization to TNFa by GalN was markedly potentiated by IL-la.8. These results suggest that suppression of the induction of ODC by GalN may be one cause of the sensitization to LPS, IL-1 or TNF, and that the induction of HDC, i.e. histamine formation, may not be involved in this sensitization.9. These results are consistent with the hypothesis that both IL-1 and TNF are involved in the sensitization to LPS.
