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

Abstract

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 μg kg−1 lipopolysaccharide (LPS) or 50 μg 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. 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. 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). 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. 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.

Localized vs. systemic inflammation in guinea pigs: a role for prostaglandins at distinct points of the fever induction pathways?

“…The fever, in this case, was biphasic. The shape of the fever curve resembled a curve after systemic treatment with LPS (32,34). Although the local formation of PGE 2 within the subcutaneous chamber was similar in response to both LPS doses (Fig.…”

“…lipopolysaccharide; febrile response; prostaglandin E 2; cyclooxygenase-2; immune system-to-brain communication MOST EXPERIMENTAL STUDIES employing bacterial lipopolysaccharide (LPS) to induce fever use a systemic route of administration, such as intraperitoneal, intravenous, or intra-arterial injections of the pyrogen. These treatments result in a generalized systemic inflammatory response, which is accompanied by increased measurable amounts of proinflammatory cytokines and LPS in the circulation (10,14,17,28,32). To study a cytokine release within a local area of inflammation, experimental models have been introduced in which LPS is administered locally, rather than systemically, into a subcutaneous air pouch in rats (8,22,23) or a subcutaneously implanted artificial Teflon chamber in guinea pigs (29,30,34).…”

Fever induction pathways: evidence from responses to systemic or local cytokine formation

“…Administration of a dimeric polyethylene glycol-linked form of the type 1 soluble receptor of TNF, a neutralizing TNF-binding protein, abolishes LPSinduced circulating bioactive TNF and causes a significant attenuation of the second phase of the febrile response (17). Intraperitoneal injection of 30 µg/kg LPS induces a similar biphasic fever in guinea pigs (lower panel of Figure 1).…”

Kinetics of the Immune Response Profile in Guinea Pigs after Vaccination withMycobacterium bovisBCG and Infection withMycobacterium tuberculosis

“…mRNA for these cytokines was detected early during the infection process, with peak IL-1␤ mRNA expression preceding that of TNF-␣ and occurring at the same time that we observed an increase in body temperature, between 25 and 35 days postinfection, in nonvaccinated animals. In other studies using the guinea pig as an animal model, others have demonstrated the dependence of the fever response on such cytokines such as IL-1␤, TNF-␣, and IL-6 (27), and thus, it appears plausible that these cytokines mediate an increase in body temperature during infection with M. tuberculosis.…”