Gene transfer with IL-4 and IL-13 improves survival in lethal endotoxemia in the mouse and ameliorates peritoneal macrophages immune competence.
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).
Baumhofer
J M
JM
University Clinic of Surgery, Vienna, Austria.
Beinhauer
B G
BG
Wang
J E
JE
Brandmeier
H
H
Geissler
K
K
Losert
U
U
Philip
R
R
Aversa
G
G
Rogy
M A
MA
D000818:Animals; D019446:Endotoxemia / Q000235:genetics / Q000276:immunology* / Q000401:mortality* / Q000628:therapy; D005260:Female; D015870:Gene Expression / Q000276:immunology; D018014:Gene Transfer Techniques; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis / Q000235:genetics*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000628:therapy; D019076:Transgenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018793:Interleukin-13; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4