Effects of pyrogenic immunomodulators on the release of corticotrophin‐releasing factor‐41 and prostaglandin E₂ from the intact rat hypothalamus in vitro

The actions of the following pyrogens: lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (Poly‐I:C), human interleukin (IL)‐1α and IL‐1β, human IL‐6 and rat interferon (INF) on corticotrophin‐releasing factor‐41 (CRF‐41) and prostanglandin E₂ (PGE₂) release from the intact rat hypothalamus in vitro have been studied. Rat hypothalami were incubated in vitro in an artificial cerebrospinal fluid. Immunoreactive (ir)‐CFR‐41 and PGE₂ released into the medium were measured by two‐site enzyme amplified immunometric assay (EAIA) and radioimmunoassay (RIA) respectively. Human IL‐6 (1 to 10,000 iu ml⁻¹) caused a dose‐dependent release of irCRF‐41, rising to a maximal 3–4 fold increase over basal at the highest dose tested. Human IL‐1α (1 to 1000 iu ml⁻¹), human IL‐1β (1 to 1000 iu ml⁻¹), poly‐I:C (10 pg ml⁻¹ to 100 μg ml⁻¹) and rat INF (1 to 10,000 IRu ml⁻¹) all failed to alter irCRF‐41 release. LPS (1 mg ml⁻¹) caused a 35% decrease in irCRF‐41 release; however, over the dose‐range of 0.1 μg ml⁻¹ to 100 μg ml⁻¹, LPS failed to alter irCRF‐41 release. The decreased irCRF‐41 release in response to LPS (1 mg ml⁻¹) was accompanied by a decrease in the subsequent 56 mm KCl stimulation of irCRF‐41. Human IL‐1α and IL‐1β (1000 iu ml⁻¹) were able to stimulate the release of irPGE₂ from intact hypothalami, causing a 2 fold increase over basal release. Poly‐I:C (100 μg ml⁻¹), LPS (0.1 μg ml⁻¹ to 1 mg ml⁻¹), rat INF (10,000 IRu ml⁻¹) and human IL‐6 (1 to 10,000 iu ml⁻¹) all failed to alter irPGE₂ release. In conclusion, these results suggest that the in vitro release of CRF‐41 and PGE₂, in response to pyrogens, are mediated via different cytokines. In view of this it is possible that different cytokines may mediate the temperature, prostaglandin and hypothalamo‐pituitary‐adrenocortical axis activation seen during pyrogenic stimulation in vivo. 1993 British Pharmacological Society