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

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).

Circulating Cytokines, Chemokines, and Stress Hormones are Increased in Patients with Organ Dysfunction Following Liver Resection

“…This hypothesis, however, is only a possible mechanism because there are no data to support systemic anergy in the present study. IL-10 may also be involved in immune depression associated with hemorrhage [26,27]. B-cells, helper T-cells, monocytes, and macrophages might be the major sources of IL-10 [28].…”

Regulation of inflammation by interleukin-4: a review of “alternatives”

“…Direct experiments in the BIAcore system have revealed that normally glycosylated mouse full-length IL-4 directly binds to human IL-4R␣ [121]. Moreover, several previous reports have shown that human full-length IL-4 is active in mouse or rat in vivo in a fashion similar to that of rodent full-length IL-4 [122,123]. We found that human full-length IL-4 is active in mice in vivo [29], but this activity is only partially similar to that of mouse full-length IL-4 [28].…”

Anti-inflammatory Cytokines and Cytokine Antagonists

“…The role of endogenous IL-4 in controlling the host septic response is unclear, although low, but significant levels of IL-4 have been detected in the serum of rabbits challenged with endotoxin and in patients with sepsis [8,117]. However, the systemic overexpression of human IL-4 in mice using cationic liposome-mediated gene transfer has recently been shown to be protective in a murine LPS/D-galactosamine-induced shock model, as survival in mice expressing the IL-4 transgene was 83%, as compared to only 20% survival in control animals [118]. This protective effect was associated with an 80% reduction in serum TNF-α levels.…”

“…Similarly, overexpression of human IL-13 by cationic liposome-mediated gene transfer in LPS/Dgalactosamine-treated mice resulted in a substantial increase in survival. In fact, IL-13 overexpression attenuated endotoxin-induced TNF-α production to a greater degree than did the systemic overexpression of human IL-4 [118]. The role(s) of IL-13 in inflammatory arthritis and IBD have not yet been defined.…”