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To explore the mechanism of endotoxin tolerance(ETT) through observing the gene expression of SOCS1 and SOCS3 in the livers of ETT rats.SD male rats were divided randomly into acute liver failure model group (ALF group) and ETT group. LPS 0.1 mg/kg (ETT group) or normal saline (ALF group) was administered five consecutive intraperitoneal injections at 24 h intervals, then, the two groups were treated with intraperitoneal injection of D-GalN 800 mg/Kg and LPS 8 microg/rat 24 h later. Liver histopathology and fine structure of rats were observed by HE staining and electron microscope. The TNF-alpha level were estimated by ELISA, the concentrations of endotoxin were determined by tachypleus amebocyte lysate and the gene expressions of SOCS1 and SOCS3 in the liver were measured by RT-PCR at 0, 2, 6, 12, 24 and 48 h after the injection of D-GalN/LPS.D-GalN/LPS induced acute liver injury was attenuated significantly in ETT group. The concentrations of endotoxin and the TNF-alpha level were evidently lower in the ETT group than those in the ALF group (endotoxin: 6 h: 1.11 +/- 0.38 vs 0.74 +/- 0.22, 24 h: 1.12 +/- 0.24 vs 0.86 +/- 0.21, all P0.05, 12 h: 1.88 +/- 0.35 vs 0.62 +/- 0.16, 48 h: 1.10 +/- 0.13 vs 0.84 +/- 0.19, all P0.01; TNF-alpha: 6 h: 86.9 +/- 12.6 vs 70.0 +/- 12.8, P0.05, 12 h: 77.0 +/- 18.1 vs 48.8 +/- 12.8, 24 h: 63.8 +/- 9.2 vs 39.1 +/- 5.7, 48 h: 53.2 +/- 8.3 vs 38.2 +/- 9.9, all P0.01). In the ALF group, the expressions of SOCS-1 and SOCS-3 were obviously higher than those in the controls and reached peak at 12th hours and 6th hours respectively. The gene expression of SOCS1 and SOCS3 in the liver in ETT group were increased significantly and much higher than those in ALF groups. (SOCS1: 6 h: 0.955 +/- 0.186 vs 1.349 +/- 0.390, 48 h: 0.766 +/- 0.145 vs 0.970 +/- 0.205, all P0.05, 2 h: 0.554 +/- 0.164 vs 0.841 +/- 0.175, 12 h: 1.130 +/- 0.181 vs 1.888 +/- 0.573, 24 h: 0.990 +/- 0.212 vs 1.550 +/- 0.439, all P0.01; SOCS3: 6 h: 0.914 +/- 0.054 vs 1.039 +/- 0.109, 12 h: 0.781 +/- 0.044 vs 0.863 +/- 0.063, all P0.05, 2 h: 0.681 +/- 0.139 vs 0.898 +/- 0.058, 24 h: 0.700 +/- 0.065 vs 0.811 +/- 0.055, all P0.01).LPS pretreatment can induce endotoxin tolerance of rats, inhibited the level of TNF-alpha and endotoxin. The up-regulation of SOCS1 and SOCS3 gene expression may be one of the possible mechanisms responsible for endotoxin tolerance.