Interleukin-1 receptor antagonist: effectiveness against interleokin-1 fever

Abstract

Conscious cats were used to examine the effectiveness of the interleukin-1 receptor antagonist against the fever induced by interleukin-1 and endotoxin. Although inactive by itself, the antagonist (three 1-micrograms bolus injections at 10-min intervals), injected into the third ventricle, attenuated the febrile response to a subsequent intracerebroventricular bolus of interleukin-1. The rise in prostaglandin E2 levels in cerebrospinal fluid, which is a characteristic feature of fever, was curtailed as well. The interleukin-1 antagonist had little or no inhibitory effect on the response to an intracerebroventricular bolus of endotoxin, even though a higher dose was employed (2-micrograms bolus injections given three times at 10-min intervals and six times at 30-min intervals, respectively, before and after endotoxin administration). At either dosage, the intracerebroventricular antagonist was completely ineffective against an intravenous bolus injection of interleukin-1 or endotoxin and both fever and prostaglandin E2 elevation developed unabated. We conclude that brain receptors mediating the pyrogenic action of centrally injected interleukin-1 are susceptible to the antagonist. The same receptors, however, are seemingly not activated by systemic pyrogens. Our findings are consistent with the concept of circulating interleukin-1 acting outside the blood-brain barrier in the normal sequence of fever.

Ciliary neurotrophic factor is an endogenous pyrogen.

“…The interaction of endogenous pyrogens with the cerebrovascular periventricular organs is likely to be a critical step in initiating the febrile response from systemically derived endogenous pyrogens, since it is unlikely that endogenous pyrogens by themselves cross the normal blood-brain barrier (5,6). The ability of an endogenous pyrogen to produce fever appears to be mediated by a common pathway involving the generation of PGE2 (reviewed in ref.…”

Interleukin‐1β stimulation of 45 Ca2+ release from rat striatal slices

“…Interestingly, the same IRAP to IL-I ratio also counteracts 95% of the fever in rabbits caused by i.v. injection of IL-I (Coceani et al, 1992). Finally, IRAP at a concentration two order of magnitudes higher than that of the IL-I, blocks IL-I binding to type I and type II receptors in different cultured cells (Rambaldi et al, 1990;Hannum et al, 1990;Dripps et al, 1991 (Nathanson et al, 1992;Berridge, 1993).…”

Suppression of Interleukin-1α-Induced Uveitis and Inhibition of Fibroblast-like Cell Proliferation by Synthetic Interleukin-1 Blockers

“…Although platelet activating factor antagonists (PAFAs) have also been developed for the same purpose, controlling inflammation, they produce diffuse actions because of the wide range of biological actions produced by PAF itself (9). One of the most exciting findings in medical science has been the discovery of certain cytokines, particularly interleukin-1 (IL-1), to produce a wide spectrum of inflammatory responses (10,11), and ofnatural interleukin-1 receptor antagonist (IL-1 ra) to antagonize all inflammatory responses induced by IL-1 (12)(13)(14)(15)(16)(17)(18). Hopefully, an ideal NSAID can be developed which is not related to arachidonate cascades.…”