title: Human recombinant interleukin-1 receptor antagonist prevents adrenocorticotropin, but not interleukin-6 responses to bacterial endotoxin in rats.
abstract: The present study was designed to analyze the role of endogenous interleukin-1 (IL-1) in the ACTH, corticosterone (CORT), and IL-6 responses of rats to bacterial endotoxin. Recombinant rat IL-1 beta (rIL-1 beta) when given ip resulted in dose-dependent increases in plasma ACTH, CORT, and IL-6 concentrations. Plasma ACTH and CORT responses could be induced by low rIL-1 beta doses that did not elevate plasma IL-6 levels. The half-maximally effective dose of rIL-1 beta was less than 0.6 microgram/kg for the ACTH and CORT responses and higher than 2.5 micrograms/kg for the IL-6 response. Time-course studies indicated that plasma ACTH and CORT concentrations were already elevated 30 min after the injection of rIL-1 beta (2.5 micrograms/kg, ip), with peak values after 1-2 h, followed by a subsequent decline. In contrast, plasma IL-6 concentrations became elevated 2 h after the injection of rIL-1 beta. In another set of experiments, the administration of endotoxin resulted in a dose-dependent elevation of the plasma ACTH, CORT, and IL-6 concentrations. The dose-response characteristics for ACTH, CORT, and IL-6 were different. The half-maximally effective dose for the ACTH and CORT, and IL-6 responses were approximately 2.5 micrograms/kg and more than 10 micrograms/kg, respectively. Time courses of plasma ACTH, CORT, and IL-6 responses to endotoxin (2.5 micrograms/kg, ip) were similar, with peak values measured after 2 h. When given alone, the human IL-1 receptor antagonist (IL-1RA; 1 or 2.5 mg/kg, ip) did not affect resting plasma ACTH and CORT concentrations and reduced plasma IL-6 concentrations in one experiment. At a dose of 1 mg/kg, IL-1RA inhibited ACTH and IL-6 responses to rIL-1 beta (2.5 micrograms/kg, ip) by 75% and 90%, respectively. Administration of IL-1RA (2.5 mg/kg, ip) 30 min after endotoxin (2.5 micrograms/kg, ip) completely prevented the ACTH response and partially inhibited the CORT response, but did not affect the IL-6 response measured 2.5 h after endotoxin administration. We conclude that 1) IL-1 receptors are involved in the ACTH and IL-6 responses to rat IL-1 beta; 2) the ACTH response, but not the IL-6 response, to a low dose dose of endotoxin in rats requires IL-1 receptor activation by endogenous produced IL-1; and 3) circulating IL-6 is not a prime mediator involved in ACTH and CORT responses to low doses of rIL-1 beta and endotoxin.
authors.affiliation: Vrije Universiteit, Faculty of Medicine, Department of Pharmacology, Amsterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Schotanus
authors.forename: F J
authors.initials: FJ
authors.lastname: Tilders
authors.forename: F
authors.initials: F
authors.lastname: Berkenbosch
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000037:antagonists & inhibitors* / Q000097:blood; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004731:Endotoxins / Q000494:pharmacology*; D004926:Escherichia coli; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D009994:Osmolar Concentration; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D000093242:Interleukin-6 Inhibitors
chemical_list: D000324:Adrenocorticotropic Hormone; D003345:Corticosterone; D004731:Endotoxins; D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D000093242:Interleukin-6 Inhibitors