Gene delivery of SOCS3 protects mice from lethal endotoxic shock.

Suppressor of cytokine signaling 3 (SOCS3) was reported as a feedback inhibitor of cytokine receptor signaling by inhibiting the JAK-STAT signal transduction pathway. We sought to test the anti-endotoxic septic shock effect of liposome mediated gene delivery of SOCS3 in a lethal endotoxic shock mouse model. BALB/c mice were injected intraperitoneally with 200 microg pcDNA3.1-SOCS3 cationic liposomes, while pcDNA3.1-IL-10 and empty vector as positive and negative control respectively. Forty-eight hours after gene delivery, mice were challenged with 4 microg of E.coli 0127:B8 LPS and 18 mg D-GalN administered i.p. 90 min later, serum TNF-alpha level was determined. Survival over the next 48 h was evaluated. Peritoneal macrophages from survival mice were stimulated in vitro with 1 ug/ml LPS for 18 h, and the supernatants were harvested for determination of the amount of TNF-alpha. We found that gene delivery of SOCS3 significantly increase the mouse survival rate from 27.8 +/- 9.6% of control group to 61.1 +/- 9.6% (p < 0.01). In comparison with control group (218 +/- 13 pg/ml) and sham delivery group (2,122 pg/ml), gene delivery of SOCS3 reduced the level of serum TNF-alpha (68 +/- 9 pg/ml) significantly (p < 0.01). Furthermore, gene delivery of SOCS3 displayed the capacity of prevention of tolerance of peritoneal macrophages to LPS. These findings suggest that gene delivery of SOCS3 mediated by liposome is a promising approach for endotoxic septic shock treatment.