Neutralization of pyrogen-induced tumour necrosis factor by its type 1 soluble receptor in guinea-pigs: effects on fever and interleukin-6 release.

1. A soluble form of the tumour necrosis factor (TNF) type 1 receptor (referred to as TNF binding protein, TNF-bp) at a dose of 1 mg per animal, or an equivalent volume of solvent, was injected together with 10 microg kg-1 lipopolysaccharide (LPS) or 50 microg kg-1 muramyl-dipeptide (MDP) directly into the arterial circulation of guinea-pigs and the effects on circulating TNF or interleukin-6 (IL-6) and on abdominal temperature were studied. 2. At 15 or 60 min after injection, LPS-induced and MDP-induced circulating TNF was below the detection limit of the assay and thus completely neutralized in animals treated with TNF-bp. In the control group, TNF was still below the limit of detection in most animals 15 min after LPS was injected; in some animals small traces of TNF could already be detected at that time. However, 60 min after administration of LPS, large amounts of TNF (19508 +/- 4682 pg ml-1) were measured in the control group. MDP-induced TNF in plasma was below the limit of detection 15 min after MDP was injected, and rose to 10862 +/- 3029 pg ml-1 60 min after injection. 3. Low levels of circulating IL-6 (20-40 international units (IU) ml-1) were measured in all groups of animals 15 min after injection of LPS or MDP. This value corresponds to the baseline activity of IL-6 in plasma of guinea-pigs. One hour after administration of LPS, IL-6 rose to 5442 +/- 1662 IU ml-1 in the control group and to a significantly lower value of 1485 +/- 179 IU ml-1 in guinea-pigs treated with TNF-bp. One hour after injection of MDP, circulating IL-6 was 2614 +/- 506 IU ml-1 in the control group, while the corresponding value in animals treated with TNF-bp again was significantly lower (873 +/- 312 IU ml-1). 4. The second phase of the characteristic biphasic LPS fever in guinea-pigs was significantly attenuated in animals treated with TNF-bp. The shorter first phase of the febrile response to LPS was identical in both groups of animals. 5. The late phase of MDP-induced fever (7-22 h after injection) was depressed by treatment with TNF-bp, while the first phase of MDP-induced fever (0-7 h after injection) was significantly enhanced by the neutralization of TNF by TNF-bp.