Endogenous monocyte chemoattractant protein-1 (MCP-1) protects mice in a model of acute septic peritonitis: Cross-talk between MCP-1 and leukotriene B-4

We investigated the involvement of monocyte chemoattractant protein (MCP)-1 in a murine model of septic peritonitis induced by cecal ligation and punc ture (CLP), Initial studies demonstrated that CLP induced a dramatic increa se in MCP-1 production in the peritoneum, followed by an increase in the re cruitment of leukocytes, MCP-1 blockade with anti-MCP-l antiserum significa ntly decreased the survival rate following CLP, which was accompanied by an enhanced recovery of viable bacteria from the peritoneum, This was likely due to the reduction in the recruitment and activation of both macrophages and neutrophils, To understand the mechanisms whereby MCP-1 may influence n eutrophil infiltration, levels of chemokines known to attract neutrophils w ere monitored, which showed that peritoneal levels of macrophage-inflammato ry protein (MIP)-2, KC, and MIP-1 alpha were not altered with anti-MCP-1 Ab s, However, anti-MCP-l Abs reduced the peritoneal levels of leukotriene B-4 (LTB4) by 59%, The i,p, injection of MCP-1 into normal mice resulted in el evated levels of LTB4 in the peritoneum, In vitro, MCP-1 stimulated the pro duction of LTB, from peritoneal macrophages, in a dose-dependent manner, A specific LTE, receptor antagonist (CP-105,696) inhibited CLP-induced recrui tment of both neutrophils and macrophages, which was accompanied by a reduc ed level of MCP-1 in the peritoneum, Finally, administration of CP-105,696 was extremely detrimental to the survival of mice following CLP, These expe riments demonstrate that endogenous MCP-1 serves as an indirect mediator to attract neutrophils via the production of LTB4, and suggest the cross-talk can occur between MCP-1 and the lipid mediator LTB, during septic peritoni tis.