Role of endogenous interleukin-1 receptor antagonist in regulating fever induced by localised inflammation in the rat

Interleukin (IL)-1 is a mediator of host defence responses to inflammation and injury, including fever, but its sites of synthesis and action have not been fully elucidated. The actions of IL-1 are antagonised by IL-1 receptor antagonist (IL-1ra). The present study tested the hypothesis that IL-1 and IL-1ra are produced locally at sites of peripheral inflammation in rats, and that endogenous IL-1ra acts to limit the fever resulting from the inflammation. Injection of lipopolysaccharide (LPS; 100 μg kg −1 ) into a subcutaneous air pouch ( i.po. ) of rats induced a significant increase in body temperature. Virtually all (∼85 %) of the injected LPS was recovered from the pouch between 1 and 8 h (when the experiment was terminated) after injection of LPS, but LPS was undetectable (< 50 pg ml −1 ) in plasma at any time. Concentrations of immunoreactive IL-1α and IL-1β were increased significantly in the pouch at 1, 2, 3, 5 and 8 h after injection of LPS, corresponding with the rise in body temperature and the fever peak. The appearance of IL-1ra was delayed until 2 h. Thereafter, the concentrations of IL-1β and IL-1ra increased in parallel with the development of fever, while the concentrations of IL-1α remained constant. IL-1ra, but not IL-1α or IL-1β, was detected in significant quantities in the plasma of LPS-injected animals. Treatment of rats with an anti-IL-1ra serum (2 ml, i.po. ) at the time of injection of LPS (10 or 100 μg kg −1 , i.po. ) abolished the appearance of IL-1ra in the circulation. Although neutralisation of endogenous IL-1ra did not affect the maximum body temperature reached after injection of submaximum (10 μg kg −1 , i.po. ) or maximum (100 μg kg −1 , i.po. ) doses of LPS, the duration of the fever was significantly prolonged, and was associated with a 3- to 4-fold increase in immunoreactive IL-1β concentrations in the pouch fluid, but not in the plasma, at the 8 h time point. These data show that effects of local ( i.po. ) injection of LPS are not due to its action in the circulation or at distant sites (such as at the blood-brain barrier). These data also show that locally produced IL-1ra, in response to injection ( i.po. ) of LPS, inhibits the production and/or action of locally produced IL-1β. The ability of IL-1ra to limit the duration, rather than the magnitude of the fever, is consistent with its delayed production, relative to IL-1. IL-1ra, therefore, appears to play a key role in the resolution of fever