EFFECTS OF PYROGENIC IMMUNOMODULATORS ON THE RELEASE OF CORTICOTROPIN-RELEASING FACTOR-41 AND PROSTAGLANDIN-E2 FROM THE INTACT RAT HYPOTHALAMUS INVITRO

1 The actions of the following pyrogens: lipopolysaccharide (LPS), polyinosinic:polycytidylic acid (Poly-I:C), human interleukin (IL)-1alpha and IL-1beta, 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. 2 Rat hypothalami were incubated in vitro in an artificial cerebrospinal fluid. Immunoreactive (ir)-CFR41 and PGE2 released into the medium were measured by two-site enzyme amplified immunometric assay (EAIA) and radioimmunoassay (RIA) respectively. 3 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-1alpha (I to 1000 iu ml-1), human IL-1beta (1 to 1000 iu ml-1), poly-I:C (10 pg ml-1 to 100 mug ml-1) and rat INF (1 to 10,000 IRu ml-1) all failed to alter irCRF-41 release. 4 LPS (I mg ml-1) caused a 35% decrease in irCRF-41 release; however, over the dose-range of 0. 1 mug ml-1 to 100 mug 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. 5 Human IL-1alpha and IL-1beta (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 mug ml-1), LPS (0. 1 mug 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. 6 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.