Circulating cytokines as mediators of fever

The febrile response is thought to be mediated by endogenous mediators, gen erically called "endogenous pyrogens," In the classical model of pathogenes is, induction of fever is mediated by the release of pyrogenic cytokines su ch as tumor necrosis factor (TNF), interleukin (IL)-1 IL-6, and interferons into the bloodstream in response to exogenous pyrogens. These mediators ac t at the level of the organum vasculosum of the lamina terminalis in the ce ntral nervous system (CNS), inducing synthesis of prostaglandins, which are the central mediators of the coordinated responses leading to fever. Howev er, analysis of recent data suggests that multiple pathways may be involved in the induction of fever by cytokines, such as local cytokine production leading to signaling through vagal fibers, release of cytokine-induced circ ulating mediators at the tissue level, the use of membrane-bound cytokines as mediators, or the local release of cytokines in the hypothalamus by circ ulating activated monocytes, In addition, certain bacterial products can st imulate cytokine production directly at the level of hypothalamus, probably by activation of Toll-like receptors. A multipathway mechanism for the ind uction of fever is therefore suggested.