The role of TNF-alpha in fever: opposing actions of human and murine TNF-alpha and interactions with IL-beta in the rat.

1. The role of tumour necrosis factor-alpha (TNF-alpha) in fever is controversial. Some studies have indicated that TNF-alpha acts as a cryogen to inhibit fever, while others suggest that TNF-alpha is an endogenous pyrogen which mediates fever. The majority of studies in experimental animals supporting a cryogenic action have been conducted using human (h)TNF-alpha, which has been shown to bind only to one (p55) of the two TNF-alpha receptors in rodents. 2. The aim of the present investigation was to study the role of TNF-alpha in fever by comparing effects of hTNF-alpha, which binds only to the p55 receptor, with those of murine (m) TNF-alpha, which binds to both p55 and p75 TNF-alpha receptors, and to investigate the relationship between TNF-alpha and interleukin-1 (IL-1), an important endogenous pyrogen. 3. Injection of hTNF-alpha (0.3-10 micrograms kg-1, i.p.) had no effect on core temperature in conscious rats (measured by remote radiotelemetry), whereas mTNF-alpha (3 micrograms kg-1) induced fever which was maximal 1 h after the injection (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls). Intracerebroventricular (i.c.v.) administration of either form of TNF-alpha elicited dose-dependent fever at doses higher than 0.12 microgram kg-1. 4. Peripheral injection of hIL-1 beta (1 microgram kg-1) resulted in fever (38.3 +/- 0.2 degree C compared to 37.2 +/- 0.1 degrees C in controls at 2 h), which was significantly attenuated (P < 0.01) by co-administration of a sub-pyrogenic dose of hTNF-alpha (1 microgram kg-1), but was unaffected by co-administration of mTNF-alpha (0.1 or 0.3 microgram kg-1, i.p.). In contrast, intracerebroventricular (i.c.v.) co-administration of a sub-pyrogenic dose (0.12 microgram kg-1) of hTNF-alpha did not attenuate fever induced by intraperitoneal (i.p.) injection of IL-1 beta, and sub-pyrogenic dose (0.12 microgram kg-1, i.c.v.) of mTNF-alpha significantly prolonged the febrile response to IL-1 beta. Pretreatment of animals with anti-TNF-alpha antiserum (i.c.v.) did not affect the febrile response to systemic IL-1 beta. 5. Animals injected i.p. with a pyrogenic dose of mTNF-alpha developed fever (38.2 +/- 0.2 degrees C compared to 37.3 +/- 0.1 degrees C in controls 2 h after the injection) that was completely abolished by peripheral administration of IL-1ra (2 mg kg-1, P < 0.001), while i.c.v. administration of IL-1ra (400 micrograms/rat) did not affect mTNF-alpha-induced fever. 6. These data indicate that endogenous TNF-alpha is probably a pyrogen and that previous results suggesting cryogenic actions of TNF-alpha resulted from the use of a heterologous protein in the rat. The markedly contrasting effects of mTNF-alpha and TNF-alpha could result from different interactions with the two TNF-alpha receptor subtypes. The data also suggest that fever induced by exogenous TNF-alpha is mediated via release of IL-1 beta in peripheral tissues, but not in the brain

Febrile response to tissue inflammation involves both peripheral and brain IL-1 and TNF-alpha in the rat.

We investigated the role and interaction between tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, and IL-6 in the development of fever and their involvement in brain and systemic pathways in response to localized tissue inflammation caused by injection of turpentine (TPS) in the rat. Intramuscular injection of 10 microl TPS caused significant increases in body temperature, of up to 2 degrees C, compared with saline-treated animals. Fevers were maximal 7-8 h after injection and were preceded by significant increases in plasma bioactive IL-6. No changes in circulating bioactive IL-1 or TNF-alpha were detected. Systemic injection of IL-1 receptor antagonist (IL-1ra, 2 mg/kg i.p.) or anti-TNF-alpha antiserum (0.4 ml i.v.) almost completely abolished the febrile responses to TPS over 8 h and markedly inhibited the rise in plasma IL-6 bioactivity measured 6 h after TPS. To test the involvement of brain cytokines, anti-TNF-alpha antiserum and IL-1ra were injected intracerebroventricularly. Injections of anti-TNF-alpha antiserum (3 microl/rat i.c.v.) or IL-1ra (400 microg/kg i.c.v.) significantly (P &lt; 0.01 and P &lt; 0.05, respectively) inhibited fever induced by TPS. These data suggest that both localized peripheral and brain IL-1 and TNF-alpha are involved directly in the pyrogenic response to inflammation. The results indicate that, in the periphery, IL-1 and TNF-alpha cause increased production of IL-6, the most likely candidate as a circulating endogenous pyrogen. </jats:p