Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans.
Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.
Granowitz
E V
EV
Department of Medicine, New England Medical Center Hospitals, Boston, MA 02111.
Porat
R
R
Mier
J W
JW
Orencole
S F
SF
Callahan
M V
MV
Cannon
J G
JG
Lynch
E A
EA
Ye
K
K
Poutsiaka
D D
DD
Vannier
E
E
D000293:Adolescent; D000328:Adult; D002452:Cell Count; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D004926:Escherichia coli; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D016207:Cytokines; D004731:Endotoxins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D003208:Concanavalin A