Chemokine C10 promotes disease resolution and survival in an experimental model of bacterial sepsis

Previous studies have suggested that the C-C chemokine C10 is involved in t he chronic stages of host defense reactions. The present study addressed th e role of C10 in a murine model of septic peritonitis, induced by cecal lig ation and puncture (CLP). Unlike other C-C chemokines, C10 levels in the pe ritoneal wash were increased approximately 30-fold above baseline levels at 48 h after CLP surgery. Immunoneutralization of peritoneal C10 Levels with polyclonal anti-C10 antiserum during CLP-induced peritonitis negatively im pacted mouse survival over 4 days. In contrast,,when 500 ng of recombinant murine C10 was administered immediately after CLP surgery, the ii-day survi val rate increased from 20% to over 60%. The C10 therapy appeared to facili tate a rapid and significant enhancement of the Levels of tumor necrosis fa ctor alpha (TNF-alpha) and monocyte chemoattractant protein-1 (MCP-I) and a later increase in interleukin-13 (IL-13) levels in the peritoneal cavity. In vitro studies showed that the combination of IL-1 beta and C10 markedly augmented TNF-alpha synthesis by peritoneal macrophages and that C10 synthe sis was induced in these cells following their exposure to IL-13, At 24 h a fter CLP surgery, only 25% of C10-treated mice were bacteremic versus 85% o f the control group that exhibited dissemination of bacteria into the circu lation, The Lack of bacteremia in C10-treated mice appeared to be related, in part, to in vitro evidence that C10 significantly enhanced the bacterial phagocytic activity of peritoneal macrophages. In addition, in vivo eviden ce suggested that C10 therapy significantly reduced the amount of material that leaked from the damaged gut. Taken together, the results of this study demonstrate that the C10 chemokine rapidly promotes disease resolution in the CLP model through its direct effects on the cellular events critically involved in host defense during septic peritonitis.