Gene transfer with IL-4 and IL-13 improves survival in lethal endotoxemia in the mouse and ameliorates peritoneal macrophages immune competence

Eur J Immunol. 1998 Feb;28(2):610-5. doi: 10.1002/(SICI)1521-4141(199802)28:02<610::AID-IMMU610>3.0.CO;2-5.

Abstract

Systemic anti-cytokine therapies have been unsuccessful in preventing mortality from gram-negative bacteremia in humans partly because of the failure to neutralize pro-inflammatory cytokines at sites of exaggerated production. In an attempt to deliver anti-inflammatory cytokines to organs directly, gene transfer was employed. Thirty-six BALB/c mice were injected intraperitoneally with cationic liposomes containing plasmids encoding the human interleukin-4 (hIL-4) or IL-13 gene. Both, hIL-4 and hIL-13 mRNA were detected by reverse transcription-polymerase chain reaction analysis in the liver and the spleen of the animals. Fourty-eight hours after the in vivo gene transfer, these 36 mice and 18 mock-transfected mice, were challenged with a lethal dose of E. coli lipopolysaccharide with D-galactosamine (D-GalN). Gene transfer with hIL-4 reduced the serum tumor necrosis factor (TNF)-alpha production in response to endotoxin/D-GalN by 80% from 113.1 pg/ml in mock-transfected animals to 22.2 pg/ml (p < 0.05); human IL-13 gene transfer reduced serum TNF-alpha levels by 90% (113.1 pg/ml to 11.6 pg/ml; p < 0.05). Survival was improved from 20% to over 83% in both treatment groups (p < 0.001). Our data demonstrate a potent in vivo anti-inflammatory action of both IL-4 and IL-13. In addition, the immune functions of peritoneal macrophages are significantly ameliorated in both treatment groups, with IL-13 demonstrating better macrophage immune modulation than IL-4 (p < 0.05).

MeSH terms

  • Animals
  • Endotoxemia / genetics
  • Endotoxemia / immunology*
  • Endotoxemia / mortality*
  • Endotoxemia / therapy
  • Female
  • Gene Expression / immunology
  • Gene Transfer Techniques*
  • Humans
  • Interleukin-13 / biosynthesis
  • Interleukin-13 / genetics*
  • Interleukin-4 / biosynthesis
  • Interleukin-4 / genetics*
  • Macrophages, Peritoneal / immunology*
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Shock, Septic / genetics
  • Shock, Septic / immunology
  • Shock, Septic / mortality
  • Shock, Septic / therapy
  • Transgenes / immunology
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Interleukin-13
  • Tumor Necrosis Factor-alpha
  • Interleukin-4