1. Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans.
- Author
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Granowitz EV, Porat R, Mier JW, Orencole SF, Callahan MV, Cannon JG, Lynch EA, Ye K, Poutsiaka DD, and Vannier E
- Subjects
- Adolescent, Adult, Cell Count, Cell Division drug effects, Concanavalin A pharmacology, Cytokines blood, Endotoxins antagonists & inhibitors, Endotoxins blood, Escherichia coli, Humans, Interleukin 1 Receptor Antagonist Protein, Lymphocyte Activation drug effects, Male, Neutrophils drug effects, Recombinant Proteins pharmacology, Sialoglycoproteins administration & dosage, Sialoglycoproteins pharmacokinetics, Endotoxins pharmacology, Interleukin-1 antagonists & inhibitors, Sialoglycoproteins pharmacology
- Abstract
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.
- Published
- 1993