HUMAN RECOMBINANT INTERLEUKIN-1 RECEPTOR ANTAGONIST PREVENTS ADRENOCORTICOTROPIN, BUT NOT INTERLEUKIN-6 RESPONSES TO BACTERIAL-ENDOTOXIN IN RATS

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-1beta (rIL-1beta) 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-1beta doses that did not elevate plasma IL-6 levels. The half-maximally effective dose of rIL-1beta was less than 0.6 mug/kg for the ACTH and CORT responses and higher than 2.5 mug/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-1beta (2.5 mug/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-10. 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 mug/kg and more than 10 mug/kg, respectively. Time courses of plasma ACTH, CORT, and IL-6 responses to endotoxin (2.5 mug/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-1beta (2.5 mug/kg, ip) by 75% and 90%, respectively. Administration of IL-1RA (2.5 mg/kg, ip) 30 min after endotoxin (2.5 ug/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-1beta; 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-1beta and endotoxin.