Interleukin-1 receptor antibody (IL-1rab) protection and treatment against lethal endotoxemia in mice.
Interleukin-1 (IL-1) is a mediator of endotoxin shock and IL-1 receptor blockade has been shown to have therapeutic efficacy against endotoxic shock and sepsis in laboratory models. The current studies were designed to characterize the efficacy of a murine monoclonal IL-1 receptor antibody (IL-1rab) against endotoxin (LPS) lethality and to investigate whether combined anticytokine therapy using the IL-1rab and a highly specific polyclonal rabbit anti-mouse TNF antibody (TNF Ab) could provide additive or synergistic efficacy against LPS lethality in C57B1/6 female mice. A single intraperitoneal (ip) dose of IL-1rab, 0.1 or 0.2 mg, significantly reduced lethality from LPS, 30 to 40 mg/kg ip, compared to nonimmune IgG, 0.1 or 0.2 mg, in control mice (P2 < 0.05). Treatment with IL-1rab was effective when administered from 6 hr before to 1 hr after LPS. After LPS, circulating levels of IL-6 were significantly lower in IL-1rab-treated mice [IL-6 (ng/ml) 2 h after LPS: IgG, 100 +/- 25, IL-1rab, 41 +/- 8; 4 h after LPS: IgG, 46 +/- 13, IL-1rab, 8 +/- 1; P2 < 0.05 and 0.03, respectively]. Northern blot analysis showed that IL-1rab markedly lowered IL-6 gene expression after LPS. Combined treatment with IL-1rab and TNF Ab did not result in any improvement in survival after LPS compared to either agent alone. These results indicate that an IL-1 receptor antibody has therapeutic efficacy against LPS and significantly decreases IL-6 production.(ABSTRACT TRUNCATED AT 250 WORDS)
McNamara
M J
MJ
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Norton
J A
JA
Nauta
R J
RJ
Alexander
H R
HR
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D004357:Drug Synergism; D004731:Endotoxins / Q000097:blood*; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000097:blood / Q000401:mortality / Q000628:therapy; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D017472:Receptors, Interleukin-1 / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D000906:Antibodies; D016207:Cytokines; D004731:Endotoxins; D017472:Receptors, Interleukin-1; D014409:Tumor Necrosis Factor-alpha