Do only circulating pyrogenic cytokines act as mediators in the febrile response? A hypothesis

The classical model of the pathogenesis of fever suggests that pyrogenic cy tokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens, represent the distal mediators of the febrile response. They are recognized at the level of the organum vasculosum of the lamina terminalis in the central nervous system, where they induce synthesis of protaglandin s representing the central mediators of the coordinated responses leading t o fever. This classical model is challenged by studies showing inconsistenc ies between the febrile response and the cytokine pattern, as well as by da ta demonstrating paradoxical hyperfebrile reactions in knock-out mice lacki ng cytokines or cytokine receptors. Moreover, no measurable cytokine concen trations are to be found in a variety of specific patients groups with febr ile conditions. There are recent data in the literature suggesting that alt ernative pathways may be involved in the induction of fever, ranging from t he use of vagal fibres to transmit the signals leading to fever, to local p roduction of cytokines at the level of the hypothalamus, or the use of memb rane-bound cytokines as mediators. A multipathway mechanism for the inducti on of fever is suggested.