Effect of age on hypothalamic prostaglandin E2 production and fever in response to tumour necrosis factor (cachectin) and endotoxin in rats.

1. Decreased febrile responses to interleukin-1 and endotoxin have been noted in a number of species with ageing. 2. The present study extends these observations by examining the pyrogenic response to intravenous recombinant human tumour necrosis factor-alpha (50 micrograms/kg) using conscious rats aged 7,20 and 80 weeks. 3. The febrile response decreased in magnitude and duration with age. Fevers of 0.9 degree C and of 5 h duration were observed in the youngest rats, whereas those aged 80 weeks were afebrile. The depression in serum zinc level and the elevation in liver zinc level, which occurred 7 h after injection, were unaffected by age. 4. The mechanism of the reduced pyrogenic response was examined by assessing prostaglandin E2 production in vitro from hypothalami of rats, aged 10 and 24 weeks, in response to Escherichia coli endotoxin and tumour necrosis factor. 5. Whereas the production of prostaglandin E2 increased by 47% and 52%, respectively, in hypothalami from 10-week-old rats, no response to either pyrogen was obtained in tissue from rats aged 24 weeks. 6. Maturity brings about a decreased responsiveness of hypothalamic prostaglandin E2 production to pyrogens, which may explain the decreased febrile responses observed.