Occurrence of interleukin-1 in cerebrospinal fluid of the conscious cat

Interleukin-1 (IL-1) is synthesized and released in response to various pathogens, including bacterial endotoxin, and is assigned an intermediary function in the genesis of fever. Its site of action in the central nervous system (CNS), however, is uncertain because the polypeptide is seemingly unable to cross the blood-brain barrier. Since several cell types, including astroglial, microglial, and vascular cells, can generate IL-1 upon appropriate stimulation, we examined whether IL-1 is formed in the CNS and may therefore serve as a messenger for systemic noxae. Experiments were conducted in the conscious cat and IL-1 was assayed in cerebrospinal fluid (CSF) from the third ventricle using a highly sensitive murine helper T cell line, D10.G4.1. In general, IL-1 levels were barely detectable in the absence of fever and did not increase at any stage of the sustained fever following intravenous injection of endotoxin (bolus) or crude monocyte supernate containing IL-1 (bolus plus infusion). In contrast, intracerebroventricular injection of a pyrogenic dose of endotoxin led to the appearance of IL-1 in the CSF. IL-1 levels reached maximal elevation during the uprise phase of the fever and declined thereafter. By the same route, natural or recombinant human IL-1 had no effect on CSF-IL-1 levels, though both preparations were as effective as endotoxin in eliciting fever. These findings confirm earlier data with radiolabelled pyrogens and indicate that the blood-brain barrier is impermeable to IL-1. We conclude that blood-borne IL-1 is likely to act at a discrete site outside the blood-brain barrier, possibly the organum vasculosum laminae terminalis. Centrally formed IL-1 may instead act diffusely in promoting fever and fever-related events (e.g. sleep).