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 l ipopolysaccharide (LPS)-induced fever in rats is induced by interleuki n-1 beta (IL-1 beta) and to determine the source of the hypothalamic I L-6 (i.e., from the periphery or from the brain). Samples of cerebrosp inal fluid were collected 60 min before and 60, 120, 180, and 240 min after the intraperitoneal injection of LPS or saline as a control. Imm ediately before the injection of LPS, anti-rat neutralizing IL-1 beta antibody (anti-IL-1 beta) or control immunoglobulin G antibody (IgG) w as microinjected into the anterior hypothalamus (AH) of each rat. At t he end of the last perfusion, blood was collected by cardiac puncture. Microinjection of anti-IL-1 beta into the AH caused a 58% reduction o f LPS fever (measured by biotelemetry). AH microinjection of anti-IL-1 beta or IgG followed by intraperitoneal injection of saline did not r esult 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 duri ng LPS fever, with the average values of IL-6 for the four post-LPS ti me 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 c ompared with the rats injected with saline (at 240 min postinjection); however, there were no differences in plasma IL-6 between rats inject ed 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 t he push-pull perfusate from the AH during LPS fever is produced at tha t site in response to a local increase in IL-1 beta and further suppor t the hypothesis that LPS-induced fever is caused by IL-1 beta-induced production of IL-6.