title: The interleukin-1 receptor antagonist can either reduce or enhance the lethality of Klebsiella pneumoniae sepsis in newborn rats.
abstract: Klebsiella pneumoniae, a worldwide cause of nosocomial infections, is one of the most common causes of death in newborns in nurseries. In this study, we investigated the role of interleukin-1 (IL-1) in an experimental animal model of neonatal sepsis, using a natural antagonist of IL-1 receptors, the IL-1 receptor antagonist (IL-1Ra), to block IL-1's effects in neonatal Klebsiella sepsis in the absence of antibiotic treatment. Newborn Wistar-Kyoto rats were injected intraperitoneally with a single dose (10 mg/kg) of either IL-1Ra (n = 43) or human serum albumin as a control (n = 40). At the same time, a 50% lethal dose of K. pneumoniae was injected subcutaneously. No antibiotics were given at any time. After 10 days, survival was 60% for the albumin group and 80% for the IL-1Ra group (P < 0.01). IL-1Ra treatment also afforded protection when the dose of bacteria was increased sixfold (P < 0.01). There were two episodes of leukopenia in the control group, which were suppressed by IL-1Ra (P < 0.01 and P < 0.001). IL-1 and IL-6 levels were lower in the IL-1Ra-treated group (P < 0.05 and P < 0.001, respectively). No differences between the two groups were observed in the number of bacteria in cultures of the blood, lungs, liver, or spleen. When IL-1Ra (10 mg/kg) was given both at time zero and 24 h after bacterial challenge, lethality was significantly increased (P < 0.01). Single doses of IL-1Ra of from 20 to 40 mg/kg progressively increased lethality compared with controls (P < 0.01) in both Wistar-Kyoto and Sprague-Dawley strain rats. In the same model, low doses of IL-1 itself (0.4 ng per rat), given 24 h prior to bacterial challenge, afforded protection (P < 0.001). These studies suggest that, in the absence of antibiotics, partial blockade of IL-1 receptors improves survival, whereas a longer or greater blockade increases lethality in newborn rats infected with K. pneumoniae.
authors.affiliation: Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: J
authors.initials: J
authors.lastname: Mancilla
authors.forename: P
authors.initials: P
authors.lastname: García
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001770:Blood Bactericidal Activity; D004305:Dose-Response Relationship, Drug; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007710:Klebsiella Infections / Q000276:immunology / Q000382:microbiology*; D007711:Klebsiella pneumoniae / Q000472:pathogenicity*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000187:drug effects; D012795:Sialoglycoproteins / Q000008:administration & dosage*
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins