title: Sites of action of IL-1 in the development of fever and cytokine responses to tissue inflammation in the rat.
abstract: 1. The objective of the present study was to determine the sites of action of the cytokine, interleukin-1 (IL-1), in the febrile response to local inflammation in the rat, by comparing the importance of IL-1 in the local tissues, the circulation and the brain. This was achieved by injecting lipopolysaccharide (LPS, 100 micrograms kg-1) into a subcutaneous air pouch and testing the effects of blocking IL-1 action with the human recombinant interleukin-1 receptor antagonist (IL-1ra) injected either into the air pouch, intraperitoneally (1 mg kg-1, 0 + 1 h, i.p.), or intracerebroventricularly (200 micrograms/rat, 0 + 1 h, i.c.v.). 2. To investigate the effect of IL-1ra on fever and the induction of local and circulating cytokines (IL-1 and IL-6), separate experiments were performed in which groups of animals were killed 1.5, 3 or 5 h after LPS injection. Plasma and pouch fluid samples were collected for bioassay of IL-1 and IL-6. 3. Injection of LPS into the air pouch significantly increased (1.5 degrees C) body temperature, local (air pouch) concentrations of bioactive IL-1 and IL-6, and circulating bioactive IL-6, compared to saline-treated controls. 4. Injection of IL-1ra into the pouch significantly attenuated LPS fever (P < 0.001). This decrease in body temperature was associated with significant inhibition of local IL-1 bioactivity 1.5 (96%), 3 (84%) and 5 h (72%), and in bioactive IL-6 in pouch lavage fluid 1.5 (45%) and 5 h (35%), after LPS injection. The concentration of bioactive IL-6 in the plasma was significantly reduced (39%) at 3 h, when temperature was approaching the maximal value. 5. Both systemic (i.p.) and central (i.c.v.) administration of IL-1ra significantly attentuated LPS fever (P < 0.05). However, it had no effect on either local concentrations of bioactive IL-1 or IL-6, or circulating IL-6, at any of the sample points. 6. These data suggest that IL-1 is released locally, at the site of tissue inflammation and that it is an important mediator of the febrile response to local inflammation. The results also indicate that IL-1 produced locally may contribute to the production of IL-6 which is released into the circulation, and that IL-1 has important actions in the generation of fever at other sites, including the brain.
authors.affiliation: School of Biological Sciences, University of Manchester.
authors.forename: A J
authors.initials: AJ
authors.lastname: Miller
authors.forename: S J
authors.initials: SJ
authors.lastname: Hopkins
authors.forename: G N
authors.initials: GN
authors.lastname: Luheshi
mesh_terms: D000818:Animals; D005334:Fever / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012795:Sialoglycoproteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha