Endogenous pyrogens in the CNS: role in the febrile response

The febrile reaction is an integrated endocrine, autonomic and behavioral response, coordinated by the hypothalamus, that includes certain components of the stress response, such as elevated corticosteroid secretion. It is produced by the actions of circulating cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), on the organum vasculosum of the lamina terminalis (OVLT), resulting in the secretion of prostaglandin E2, which initiates a variety of responses, including elevation of body temperature and corticosteroid secretion. Although circulating cytokines apparently do not enter the brain, injections of IL-1 or TNF well within the blood-brain barrier produce identical effects. We have examined the localization of possible central sources of cytokines and prostaglandins, using immunohistochemistry, immunoblotting and enzyme assay. Our data indicate that in the brain cyclooxygenase, the key enzyme in the synthesis of prostaglandins, is found in neurons in the OVLT, but is also made by neurons in many sensory and visceral regulatory systems. We present evidence also that IL-1 beta in the human brain and TNF alpha in the mouse may be present in the central nervous system as neuromodulators that are important for producing the autonomic, endocrine and behavioral components of the febrile reaction. We propose a sequence of events in the febrile reaction involving: (1) action of circulating cytokines on cyclooxygenase containing neurons within the OVLT to produce local prostaglandin secretion; (2) local diffusion of prostaglandin E2 into the preoptic and anterior hypothalamic areas; (3) action of prostaglandin E2 on cytokine containing neurons in the preoptic and anterior hypothalamic areas; and (4) release of cytokines from neuronal terminals at distal sites involved in producing the autonomic, endocrine and behavioral components of the febrile reaction.