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

Article date: August 1996

By: Andreas Stefferl, Stephen J. Hopkins, Nancy J. Rothwell, Giamal N. Luheshi, in Volume 118, Issue 8, pages 1919-1924

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

DOI: 10.1111/j.1476-5381.1996.tb15625.x

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