A fall in plasma
iron level and an increase in
copper level were observed in rabbits subsequent with the febrile response induced by an
intravenous administration of
muramyl dipeptide, AcMur-L-Ala-D-isoGln (MDP). The pyrogenic activity of MDP was due partly to the induction of circulating
endogenous pyrogen (EP). EP produced in vitro by activated macrophages also elicited changes in
iron and
copper levels in rabbits. Nonpyrogenic MDP derivatives
murabutide [MDP(Gln)-OnBu] and the stereoisomer of MDP [MDP(
D,D)] did not cause any change in blood
metal levels. Another adjuvant and nonpyrogenic analogue,
murametide [MDP(Gln)-OMe], elicited hypoferremia and hypercupremia.
Murametide, which has been previously shown to induce secretion of circulating EP but prevents in vivo
fever response, was unable to prevent an EP-induced effect on plasma
metal concentrations. Injection of supernatant fluids of macrophages incubated with these different
glycopeptides showed that only compounds able to induce EP release were capable of evoking hypoferremia and hypercupremia. The EP-containing fluid was 10-fold more active on change in temperature and in plasma
metal levels when it was given intracerebroventricularly compared with intravenously. In contrast, a pyrogenic dose of MDP that can act directly on the central thermoregulatory structures did not modify
iron and
copper levels when it was injected intracerebroventricularly.