Fever and production of cytokines in response to repeated injections of muramyl dipeptide in guinea-pigs.
Fever and systemic plasma levels of the cytokines tumour necrosis factor alpha (TNF) and interleukin-6 (IL-6) were measured in guinea-pigs in response to single or repeated intramuscular injections of 100 micrograms/kg muramyl-dipeptide (MDP). In a pilot study (experiment 1), MDP-induced fever was monitored for 8 h. The first fever phase 90-360 min after injection of MDP was followed by the second phase which continued beyond the duration of this experiment. High circulating levels of TNF and IL-6 were detected just before body core temperature started to rise. Within the next 90 min TNF declined again by more than 90% while IL-6 remained elevated. In experiment 2, the effects of repeated injections of MDP (5 times at intervals of 3 days) on the same parameters were investigated. In this paradigm, the febrile response started earlier (60 min after injection) and the first phase of fever remained manifest until 360 min after injection, while the late phase, measured 360-720 min after injection, was attenuated. Circulating, bioactive TNF and IL-6, measured 60 and 180 min after MDP was administered, were the same in response to the first, third, and fifth injection. In experiment 3, the influence of five repeated MDP injections on the abdominal temperature was measured for 22 h, and circulating cytokines were analysed before (360 min after injection) and during (480 min after injection) the late phase of MDP-induced fever. The late phase of MDP-induced fever 7-22 h after injection was attenuated in response to the second and further administrations of this pyrogen. At 6 h after the first, third, and fifth administration of MDP, only traces of TNF alpha were measured, 2 h later no bioactive TNF was detected at all. At these times also IL-6 declined again, compared with the activity of this cytokine measured during the early phase of MDP fever, but was still present in elevated amounts. Compared with the values measured in response to the third and fifth injections of MDP, circulating IL-6 was higher 360 min and 480 min after the first injection. It remains speculative whether the longer duration of elevated IL-6 in plasma is related to the development of the long-lasting, late phase of MDP-induced fever, which was only observed after the first of five repeated injections of MDP at intervals of 3 days.