Changes of abdominal temperature and circulating levels of cortisol and interleukin-6 in response to intra-arterial infusions of tumor necrosis factor-alpha or tumor necrosis factor-beta in guinea pigs.

The sister proteins tumor necrosis factor (TNF)-alpha and TNF-beta share 35% of their amino acid sequence and a number, but not all, of their biological properties. In the present study we infused amounts of 5 microg/kg TNF-alpha, TNF-beta (both preparations with identical bioactivities) or of solvent (0.9% sterile saline) into the circulation of guinea pigs and studied the effects on abdominal temperature, on the induction of endogenous formation of interleukin-6 and on levels of cortisol in plasma as a parameter of the activation of the hypothalamic-pituitary-adrenal axis. Infusion of TNF-alpha and TNF-beta both resulted in identical circulating TNF-like-activities corresponding to an amount of about 7000 pg/ml. TNF-alpha induced a biphasic fever lasting for more than 6 h, while in response to TNF-beta just the shorter first phase of fever (duration: 120 min) was measured. Circulating interleukin-6 (baseline level: 12-20 International Units (I.U.)/ml) and cortisol (baseline level: 70-120 ng/ml) increased about 6-fold during the first phase of the febrile response 60 min after the start of infusion with TNF-alpha or TNF-beta. Thereafter interleukin-6 and cortisol declined again in response to TNF-beta, but further increased after infusion with TNF-alpha to peak values measured 3 h after the start of infusion (interleukin-6: 258 +/- 52 I.U./ml; cortisol: 790 +/- 167 ng/ml). In animals infused with solvent abdominal temperature and interleukin-6 remained at the baseline values, just cortisol increased slightly. The results demonstrate that TNF-alpha is a much stronger inducer of fever and interleukin-6 production or of HPA-axis activation than TNF-beta in so far as all the investigated responses can be measured for prolonged time in response to TNF-alpha.