Inhibition Of Cyclooxygenase-2Suppresses Accumulation And Activation Of Myeloid Derived Suppressor Cells And Partially Restores T Cell Dysfunction In Septic Mice

Objective:The accumulation and activation of myeloid derived suppressor cells (MDSCs) plays crucial role in sepsis-induced immunosuppression. However, little is known about the mechanisms underlying the expansion and activation of MDSC in sepsis. Activation of Cyclooxygenase-2(Cox-2) has been related to expansion of regulatory immune cells, e.g. Myeloid derived suppressor cells (MDSCs) and regulatory T lymphocytes (Treg), etc, in divergent malignancies. But to date, the role of Cox-2in the expansion of MDSC in sepsis has not been reported.Methods:In the present study, we used a murine cecal ligation and puncture (CLP) model to determine the effect of a specific cox-2inhibitor, NS398(20mg/kg, intraperitoneally injected), on the accumulation of MDSC, apoptosis and proliferation of T lymphocytes and delayed type hypersensitivity (DTH) reaction. The susceptibility to secondary infection of mice was also evaluated by inoculation of Pseudomonas Auraginosa following CLP.Results:NS398significantly decreased the number and percentage of MDSC in spleen, and bone marrow in septic mice at7days (P<0.05) and14days post CLP (P<0.01), but not in peripheral blood. NS398promoted proliferation of CD3+T lymphocytes of septic mice. However, it does not affect the apoptosis of CD3+T lymphocytes. NS398treatment also partially restored DTH of septic mice (P<0.05). Moreover, NS398increased resistance of mice to secondary infection of P.auraginosa. This effect could be counteracted by adoptive transfer of CD11b+Gr-1+cells isolated from septic mice.Conclusion:The data indicated that Cox-2play a pivotal role in the accumulation of MDSCs, which in turn, contribute to the onset of immunosuppression in sepsis. Cox-2could be a promising target for the modulation of immunosuppression in sepsis.