INTERLEUKIN-1-BETA CAUSES THE INCREASE IN ANTERIOR HYPOTHALAMIC INTERLEUKIN-6 DURING LPS-INDUCED FEVER IN RATS

The purpose of this study was to determine, using push-pull perfusion, whether the central pyrogenic action of interleukin-6 (IL-6) during lipopolysaccharide (LPS)-induced fever in rats is induced by interleukin-1 beta (IL-1 beta) and to determine the source of the hypothalamic IL-6 (i.e., from the periphery or from the brain). Samples of cerebrospinal fluid were collected 60 min before and 60, 120, 180, and 240 min after the intraperitoneal injection of LPS or saline as a control. Immediately before the injection of LPS, anti-rat neutralizing IL-1 beta antibody (anti-IL-1 beta) or control immunoglobulin G antibody (IgG) was microinjected into the anterior hypothalamus (AH) of each rat. At the end of the last perfusion, blood was collected by cardiac puncture. Microinjection of anti-IL-1 beta into the AH caused a 58% reduction of LPS fever (measured by biotelemetry). AH microinjection of anti-IL-1 beta or IgG followed by intraperitoneal injection of saline did not result in significant change in core body temperature. AH injection of anti-IL-1 beta also resulted in a 97% reduction in AH IL-6 levels during LPS fever, with the average values of IL-6 for the four post-LPS time points being 113 +/- 50 U/ml for the rats injected with IgG and LPS and 3 +/- 2 U/ml for the rats injected with anti-IL-1 beta and LPS (P = 0.024). Injection of LPS led to a significant rise in plasma IL-6 compared with the rats injected with saline (at 240 min postinjection); however, there were no differences in plasma IL-6 between rats injected with IgG and LPS and rats injected with anti-IL-1 beta and LPS (P = 0.479). These data support the hypothesis that the IL-6 measured in the push-pull perfusate from the AH during LPS fever is produced at that site in response to a local increase in IL-1 beta and further support the hypothesis that LPS-induced fever is caused by IL-1 beta-induced production of IL-6.