Pyrogenic effects of cytokines (IL-1β, IL- 6, TNF-α) and their mode of action on thermoregulatory centers and functions

Abstract The objective of this study was to compare the thermoregulatory responses of rabbits to fever-inducing doses of various cytokines (IL-1 β , IL-6, TNF- α ) injected peripherally (i.v.), or centrally (i.h.). TNF- α (1 μg kg −1 ), when applied i.v. at thermoneutral conditions, induced a long lasting increase in hypothalamic temperature, which reached maximal values within 50 min and then persisted for at least 3 h. This monophasic fever-like response was due to extensive and long lasting attenuation of panting and due to transient vasoconstriction. Metabolic rate tended to increase during the early phase of the fever, only. On the other hand, IL-6 when applied i.v. in the same dose (1 μg kg −1 ) and IL-1 β , in a much lower dose (60 ng kg −1 ), induced a short lasting monophasic hyperthermia due to transient attenuation of panting and due to transient vasoconstriction. No significant increase in metabolic rate was observed. The immediate attenuation of panting and induction of vasoconstriction rather resembled reflex (shock) responses than specific thermoregulatory reactions. Thirty minutes after i.v. administration of TNF- α , temperature thresholds for induction of cold thermogenesis, panting and vasomotion were shifted to higher body temperatures and remained elevated for at least 3 h. In case of IL-1 β the increased temperature thresholds were observed 30 min after i.v. administration, only. I.v. applied IL-6 did not influence the thresholds neither 30 or 180 min after injection. Thus, peripheral IL-6 rather induced hyperthermia than fever. When injected i.h. all cytokines studied induced a long lasting increase in body temperature similar to that after i.v. injection of LPS. Temperature thresholds for induction of all thermoregulatory outputs were increased and remained increased for at least 3 h. No changes in hypothalamic thermosensitivity were observed. Data indicate a nonspecific effect of central cytokines on body temperature control. IL-1 β appeared to be the most potent fever inducer. Nanogram doses of IL-1 β injected i.v. induced a similar febrile response as microgram doses of other cytokines. On the other hand, TNF- α induced a longer lasting fever than other cytokines.