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We studied the effects of tolerance induced by Escherichia coli-derived LPS on the innate immune response to a subsequent Staphylococcus aureus bacterial challenge. LPS tolerance was induced in wild-type mice by either intraperitoneal or intravenous injection of 2 μg of LPS on 2 consecutive days. Mice were challenged with an intravenous injection of live S. aureus (5 × 108 colony-forming units) 2 days after the second LPS dose. LPS-tolerant mice had a diminished serum interferon-γ response to the bacterial challenge. Bacterial counts in liver and spleen tissues were decreased, and survival was improved after the Staphylococcus challenge in LPS-tolerant mice compared with saline-pretreated control mice. LPS pretreatment by the intravenous route was also associated with a decreased number of bacterial colonies in lung tissue in addition to liver and spleen, suggesting that induction of LPS tolerance was somewhat compartmentalized after intraperitoneal LPS pretreatment. Induction of tolerance seemed to be due to LPS-specific signaling because LPS pretreatment of LPS-nonresponsive C3H/HeJ mice did not provide similar effects after bacterial challenge. Flow cytometric analysis of spleens from LPS-tolerant mice revealed an increase in phagocytic cells (neutrophils and macrophages) compared with control mice. Ex vivo culture of splenocytes from LPS-tolerant mice demonstrated increased uptake of fluorescein isothiocyanate-tagged ovalbumin, but no difference in either phagocytosis of fluorescein isothiocyanate-labeled Staphylococcus or bactericidal activity could be demonstrated on a per-cell basis. These results show that attenuation of inflammation and mortality during LPS tolerance extends to gram-positive bacterial organisms and suggests that LPS-induced enhancement of the innate immune response may be attributed to increased numbers of phagocytic cells.