Macrophage-derived chemokine (MDC), a recently identified CC chemokine, has been regarded to be involved in chronic inflammation and dendritic cell and lymphocyte homing. In this study, we demonstrate a pivotal role for MDC during experimental sepsis induced by cecal ligation and puncture (CLP). Intraperitoneal administration of MDC (1 microg/mouse) protected mice from CLP-induced lethality. The survival was accompanied by increased number of peritoneal macrophages and decreased recovery of viable bacteria from the peritoneum and peripheral blood. In addition, mice treated with an i.p. injection of MDC cleared bacteria more effectively than those in the control when 3 x 108 CFU live Escherichia coli was i.p. inoculated. Endogenous MDC was detected in the peritoneum after CLP, and neutralization of the MDC with anti-MDC Abs decreased CLP-induced recruitment of peritoneal macrophages and increased the recovery of viable bacteria from the peritoneum and peripheral blood. MDC blockade was deleterious in the survival of mice after CLP. In vitro, MDC enhanced the phagocytic and killing activities of peritoneal macrophages to E. coli and induced both a respiratory burst and the release of lysozomal enzyme from macrophages. Furthermore, MDC dramatically ameliorated CLP-induced systemic tissue inflammation as well as tissue dysfunction, which were associated in part with decreased levels of TNF-alpha, macrophage inflammatory proteins-1alpha and -2, and KC in specific tissues. Collectively, these results indicate novel regulatory activities of MDC in innate immunity during sepsis and suggest that MDC may aid in an adjunct therapy in sepsis.