Suppressor of cytokine signaling 3 (SOCS3) was reported as a feedback inhibitor of cytokine receptor signaling byinhibiting the JAK-STAT signal transduction pathway.We sought to test the anti-endotoxic septic shock effect ofliposome mediated gene delivery of SOCS3 in a lethal endotoxic shock mouse model.BALB/c mice were injectedintraperitoneally with 200 μg pcDNA3.1-SOCS3 cationic liposomes,while pcDNA3.1-IL-10 and empty vector aspositive and negative control respectively.Forty-eight hours after gene delivery,mice were challenged with 4 μg ofE.coli 0127:B8 LPS and 18 mg D-GaIN administered i.p.90 min later,serum TNF-α level was determined.Survivalover the next 48h was evaluated.Peritoneal macrophages from survival mice were stimulated in vitro with 1 μg/mlLPS for 18h,and the supernatants were harvested for determination of the amount of TNF-α.We found that genedelivery 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±13pg/ml) and sham delivery group (219±22pg/ml),genedelivery of SOCS3 reduced the level of serum TNF-α(68±9pg/ml) significantly(p<0.01).Furthermore,genedelivery of SOCS3 displayed the capacity of prevention of tolerance of peritoneal macrophages to LPS.Thesefindings suggest that gene delivery of SOCS3 mediated by liposome is a promising approach for endotoxic septicshock treatment.Cellular & Molecular Immunology.2005;2(5):373-377. 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 library-mediated gene delivery of SOCS3 in a lethal endotoxic shock mouse model.BALB / c mice were injected intravenously with 200 μg pcDNA3.1-SOCS3 cationic liposomes, while pcDNA3.1-IL-10 and empty vector aspositive and negative control respectively. Forty-eight hours after gene delivery, mice were challenged with 4 μg ofE.coli 0127: B8 LPS and 18 mg D-GaIN administered ip 90 min later, serum TNF-α level was determined. Survivalover the next 48h was evaluated. Peritoneal macrophages from survival mice were stimulated in vitro with 1 μg / ml LPS for 18h , and the supernatants were harvested for determination of the amount of TNF-α. We found that the gene expression of SOCS3 significantly increased the mouse survival rate from 27.8 ± 9.6% of control groups to 61.1 ± 9.6% (p <0.01) .In (p <0.01) compared with control group (218 ± 13 pg / ml) and sham delivery group (219 ± 22 pg / ml) .Furthermore, genedelivery 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 septics shock treatment. Cellular & Molecular Immunology. 2005; 2 (5): 373-377 .