MCP-1 PROTECTS MICE IN LETHAL ENDOTOXEMIA

The overzealous production of proinflammatory cytokines in sepsis can result in shock, multiorgan dysfunction, and even death. In this study , we assessed the role of monocyte chemoattractant protein-1 (MCP-1) a s a mediator of sepsis in endotoxin-challenged mice. Intraperitoneal a dministration of LPS to CD-1 mice induced a substantial time-dependent increase in MCP-1 in plasma, lung, and liver. The passive immunizatio n of mice with rabbit antimurine MCP-1 antiserum 2 h before endotoxin administration resulted in a striking increase in LPS-induced mortalit y from 10% in control animals to 65% in anti-MCP-1-treated animals. Im portantly, the administration of anti-MCP-1 antibodies to endotoxin-ch allenged mice resulted in increases in peak TNF-alpha and IL-12 levels , and also in a trend toward decreased serum levels of IL-10. Converse ly, the administration of recombinant murine MCP-1 intraperitoneally s ignificantly protected mice from endotoxin-induced lethality, and resu lted in an increase in IL-10 levels, a decrease in IL-12 levels, and a trend toward decreased levels of TNF. In conclusion, our findings ind icate that MCP-1 is a protective cytokine expressed in murine endotoxe mia, and does so by shifting the balance in favor of antiinflammatory cytokine expression in endotoxin-challenged animals.