SITES OF ACTION OF IL-1 IN THE DEVELOPMENT OF FEVER AND CYTOKINE RESPONSES TO TISSUE INFLAMMATION IN THE RAT

1 The objective of the present study was to determine the sites of act ion 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 mu g kg(-1)) into a subcutaneo us 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 mu g/rat, 0 + 1 h, i.c.v.). 2 T o 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 L PS injection. Plasma and pouch fluid samples were collected for bioass ay of IL-1 and IL-6. 3 Injection of LPS into the air pouch significant ly increased (1.5 degrees C) body temperature, local (air pouch) conce ntrations of bioactive IL-1 and IL-6. and circulating bioactive IL-6, compared to saline-treated controls. 4 Injection of IL-1ra into the po uch significantly attenuated LPS fever (P<0.001). This decrease in bod y 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 i n pouch lavage fluid 1.5 (45%) and 5 h (35%), after LPS injection. The concentration of bioactive IL-6 in the plasma was significantly reduc ed (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 si gnificantly attentuated LPS fever (P<0.05). However, it had no effect on either local concentrations of bioactive IL-1 or IL-6, or circulati ng IL-6, at any of the sample points. 6 These data suggest that IL-1 i s released locally. at the site of tissue inflammation and that it is an important mediator of the febrile response to local inflammation. T he results also indicate that IL-1 produced locally may contribute to the production of IL-6 which is released into the circulation, and tha t IL-1 has important actions in the generation of fever at other sites , including the brain.