LAUSR

&NA; Previous studies have shown that pretreatment with thapsigargin (TG), a cellular stress inducer, produced potent protective actions against various pathologic injuries. So far there is no information on the effects of TG on the development of bacterial sepsis. Using lipopolysaccharides‐ and cecal ligation/puncture‐induced sepsis models in mice, we demonstrated that preconditioning with a single bolus administration of TG conferred significant improvements in survival. The beneficial effects of TG were not mediated by ER stress induction or changes in Toll‐like receptor 4 signaling. In vivo and in cultured macrophages, we identified that TG reduced the protein production of pro‐inflammatory cytokines, but exhibited no significant effects on steady state levels of their transcriptions. Direct measurement on the fraction of polysome‐bound mRNAs revealed that TG reduced the translational efficiency of pro‐inflammatory cytokines in macrophages. Moreover, we provided evidence suggesting that repression of the mTOR (the mammalian target of rapamycin) signaling pathway, but not activation of the PERK (protein kinase R‐like endoplasmic reticulum kinase)‐eIF2&agr; (eukaryotic initiation factor 2&agr;) pathway, might be involved in mediating the TG effects on cytokine production. In summary, our results support that pharmacological preconditioning with TG may represent a novel strategy to prevent sepsis‐induced mortality and organ injuries.