The role of TNF-α in fever: opposing actions of human and murine TNF-α and interactions with IL-β in the rat

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