• Z J Liu, X L Liu, J Zhao, Y J Shi, L N Yan, X F Chen, X H Li, H B You, F L Xu, and J P Gong.
• Center of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, PR China.
• Dig Liver Dis. 2008 Jul 1;40(7):568-77.

BackgroundEndotoxin tolerance is an important mechanism to maintain the homeostasis of liver. It was reported that suppressors of cytokine signalling-1 was a negative regulator of lipopolysaccharide-induced macrophages activation, however, the mechanism underlying endotoxin tolerance and suppressors of cytokine signalling-1 has not been fully elucidated.AimOur aim here is to clarify whether suppressors of cytokine signalling-1 was involved in the mechanisms of endotoxin tolerance in liver through dampening nuclear factor-kappaB-mediated pathway.MethodsEndotoxin tolerance models of C57BL/6J mice and isolated Kupffer cells were established by pretreating them with a low dose of lipopolysaccharide to observe the changes of suppressors of cytokine signalling-1 expression during endotoxin tolerance inducement. Moreover, a vector-based short hairpin RNA expression system was used to specifically inhibit suppressors of cytokine signalling-1 expression in RAW264.7 macrophage cells to further explore the role of suppressors of cytokine signalling-1 in endotoxin tolerance inducement. The expression of suppressors of cytokine signalling-1 was analysed by immunohistochemistry, reverse transcription-polymerase chain reaction and Western blotting, respectively. The responses to lipopolysaccharide were assessed by the activation of nuclear factor-kappaB and the production of tumour necrosis factor-alpha, which were analysed by ELISA.ResultsThe histopathologic changes in the liver of the non-endotoxin tolerance group were more serious than those of the endotoxin tolerance group. The phagocytic activity of Kupffer cells were depressed and suppressors of cytokine signalling-1 expression in the endotoxin tolerance group obviously increased. Endotoxin tolerance also led to a hyporesponse of Kupffer cells to lipopolysaccharide with less activation of nuclear factor-kappaB, less production of tumour necrosis factor-alpha and more expression of suppressors of cytokine signalling-1 than those of non-endotoxin tolerance group. Moreover, the inhibitive effect was partly refracted in pSOCS-1-short hairpin RNA transfected RAW264.7 cells.ConclusionsEndotoxin tolerance induced by lipopolysaccharide pretreatment was accompanied with upregulation of suppressors of cytokine signalling-1 and the silence of suppressors of cytokine signalling-1 by RNA interference obviously attenuated this inhibitive effect, indicating that the absence of suppressors of cytokine signalling-1 caused abnormal enhancement of inflammatory cytokine production and suppressors of cytokine signalling-1 was involved in endotoxin tolerance inducement through dampening nuclear factor-kappaB-mediated pathway. Therefore, suppressors of cytokine signalling-1 may be a new target for the clinical treatment of sepsis.

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