Inhibition Of IL-6 Trans-Signaling Mitigates Immuno-Inflammatory Response And Improves Cognitive Dysfunction In Sepsis Mice

Part 1 Inhibition of IL-6 trans-signaling supresses inflammation and regulates immune cells in mice with sepsisObjective:To investigate effects of IL-6 trans-signaling on immuno-inflammatory regulation in mice with sepsis.Methods:Eighty mice were divided randomly into four groups:sham group(n=15),CLP group(n=30),CLP+sgp130Fc group(n=20)and sgp130Fc group(n=15).CLP was used to induce sepsis.Sgp130Fc 0.5mg/kg was injected intraperitoneally 1 hour after CLP in the CLP+sgp130Fc group and sgp130Fc group.Survival rate and body weight were monitored during the entire research period(10 d)daily.At 24 h after CLP,IL-6,IL-10,MCP-1 and TNFαlevels were detected by ELISA;Peripheral blood leukocytes were separated and lymphocyte subgroups were tested by the flow cytometry marked by the immunofluorescent monoclonal antibody.Results:Compared with sham group,the survival rate and body weight on day 2-10 of sepsis mice were decreased significantly(P<0.05);at 24 h after CLP,the expressions of IL-6,IL-10,MCP-1 and TNFαwere increased significantly(P<0.05)in the CLP group.There were lower levels of the CD3~+CD4~+T cell and CD45~+CD19~+B cell but higher level of the CD3~+CD8~+T cell in the CLP group(P<0.05).Compared with the CLP group,the survival rate on day 3-10 of mice were increased significantly(P<0.05);at 24 h after CLP,the expressions of IL-6,IL-10,MCP-1 and TNFαwere decreased significantly and there were higher levels of the CD3~+CD4~+T cell and CD45~+CD19~+B cell but lower level of the CD3~+CD8~+T cell in the CLP+sgp130Fc group(P<0.05).But sgp130Fc had no significant effect on the body weight in the sepsis mice(P>0.05).Conclusions:Inhibition of IL-6 trans-signaling can reduce mortality of mice with sepsis,possibly associated with regulation of early peripheral blood lymphocyte subgroup and inhibition of inflammatory responses.Part 2 Inhibition IL-6 trans-signaling with sgp130Fc improves cognitive dysfunction in septic mice by reducing damage to the BBB.Objective:To investigate the effect of IL-6 trans-signaling on cognition and neurobehavior on mice with sepsis.Methods:Eighty SPF male C57BL/6J mice were selected and CLP was used to induce sepsis.The mice were divided randomly into four groups:sham group(n=10),CLP group(n=35),CLP plus sgp130Fc group(n=25)and sgp130Fc group(n=10).Sgp130Fc 0.5 mg/kg was injected intraperitoneally 1 h after sham operation or CLP in the sgp130Fc group and CLP+sgp130Fc group.Neural function scores of mice were monitored during the entire research period(10d)daily.Hippocampus tissues were obtained at 24 h after sham operation or CLP for the protein expression of occludin by Western blot.The cognitive function of mice was measured by Morris water maze on the 4th day after sham operation or CLP.Results:Compared with the sham group,the neural function scores on day 2-10 of mice were decreased significantly(P<0.05),the expression of occludin was down-regulated(P<0.05),and times of crossing the platform and the time in target quadrant during the morris water maze(MWM)test were decreased significantly in the CLP group(P<0.05);there was no significant difference in the above indexes in sgp130Fc group(P>0.05).Compared with the CLP group,the neural function scores on day 3-10 of mice were increased significantly(P<0.05),the expression of occludin was up-regulated(P<0.05),and times of crossing the platform and the time in target quadrant during the morris water maze(MWM)test were increased significantly in the CLP+sgp130Fc group(P<0.05).Conclusion:Inhibition of IL-6 trans-signaling can alleviate the damage of the BBB and improve cognition of mice with sepsis.