THE ROLE OF TNF-ALPHA IN FEVER - OPPOSING ACTIONS OF HUMAN AND MURINETNF-ALPHA AND INTERACTIONS WITH IL-BETA IN THE RAT

1 The role of tumour necrosis factor-alpha (TNF-alpha) in fever is con troversial. Some studies have indicated that TNF-alpha acts as a cryog en to inhibit fever, while others suggest that TNF-alpha is an endogen ous pyrogen which mediates fever. The majority of studies in experimen tal animals supporting a cryogenic action have been conducted using hu man (h)TNF-alpha, which has been shown to bind only to one (p55) of th e two TNF-alpha receptors in rodents. 2 The aim of the present investi gation was to study the role of TNF-alpha in fever by comparing effect s of hTNF-alpha, which binds only to the p55 receptor, with those of m urine (m)TNF-alpha, which binds to both p55 and p75 TNF-alpha receptor s, and to investigate the relationship between TNF-alpha and interleuk in-1 (IL-1), an important endogenous pyrogen. 3 Injection of hTNF-alph a (0.3-10 mu g kg(-1), i.p.) had no effect on core temperature in cons cious rats (measured by remote radiotelemetry), whereas mTNF-alpha (3 mu g 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 TN F-alpha elicited dose-dependent fever at doses higher than 0.12 mu g k g(-1). 4 Peripheral injection of hIL-1 beta (1 mu g kg(-1)) resulted i n fever (38.3 +/- 0.2 degrees C compared to 37.2 +/- 0.1 degrees C in controls at 2 h), which was significantly attenuated (P<0.01) by co-ad ministration of a sub-pyrogenic dose of hTNF-alpha (1 mu g kg(-1)), bu t was unaffected by co-administration of mTNF-alpha (0.1 or 0.3 mu g k g(-1), i.p.). In contrast, intracerebroventricular (i.c.v.) co-adminis tration of a sub-pyrogenic dose (0.12 mu g kg(-1)) of hTNF-alpha did n ot attenuate fever induced by intraperitoneal (i.p.) injection of IL-1 beta, and sub-pyrogenic dose (0.12 mu g kg(-1), i.c.v.) of mTNF-alpha significantly prolonged the febrile response to IL-1 beta. Pretreatme nt of animals with anti-TNF-alpha antiserum (i.c.v.) did not affect th e 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 injecti on) that was completely abolished by peripheral administration of IL-1 ra (2 mg kg(-1), P<0.001), while i.c.v. administration of IL-1ra (400 mu g/rat) did not affect mTNF-alpha-induced fever. 6 These data indica te that endogenous TNF-alpha is probably a pyrogen and that previous r esults suggesting cryogenic actions of TNF-alpha resulted from the use of a heterologous protein in the rat. The markedly contrasting effect s of mTNF-alpha: and hTNF-alpha could result from different interactio ns with the two TNF-alpha receptor subtypes. The data also suggest tha t fever induced by exogenous TNF-alpha is mediated via release of IL-1 beta in peripheral tissues, but not in the brain.