Sepsis causes over 200,000 deaths yearly in the US; better treatments are urgently needed. Administering bone marrow stromal cells (BMSCs—also known as mesenchymal stem cells) to mice before or shortly after inducing sepsis by cecal ligation and puncture reduced mortality and improved organ function. The beneficial effect of BMSCs was eliminated by macrophage depletion or pretreatment with antibodies specific for interleukin-10 (IL-10) or IL-10 receptor. Monocytes and/or macrophages from septic lungs made more IL-10 when prepared from mice treated with BMSCs versus untreated mice. Lipopolysaccharide (LPS)-stimulated macrophages produced more IL-10 when cultured with BMSCs, but this effect was eliminated if the BMSCs lacked the genes encoding Toll-like receptor 4, myeloid differentiation primary response gene-88, tumor necrosis factor (TNF) receptor-1a or cyclooxygenase-2. Our results suggest that BMSCs (activated by LPS or TNF-α) reprogram macrophages by releasing prostaglandin E2 that acts on the macrophages through the prostaglandin EP2 and EP4 receptors. Because BMSCs have been successfully given to humans and can easily be cultured and might be used without human leukocyte antigen matching, we suggest that cultured, banked human BMSCs may be effective in treating sepsis in high-risk patient groups.
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We would like to thank M.J. Brownstein for continuous advice and discussions; J. M. Weiss (NCI, NIH) for supplying the Ifng−/− mice; A. Keane-Myers (NIAID) for supplying the Il10−/− mice; Christophe Cataisson (NCI) for supplying the Tnfrsf1a−/− and Tnfrsf1b−/− mice; T. Merkel (US Food and Drug Administration) for supplying the Tlr4−/− and Myd88−/− mice; K. Holmbeck and L. Szabova (NIDCR) for the FVB/NJ mouse cells; and I. Szalayova and S. Key (NIDCR) for their superb technical help. The research was supported by the intramural programs of the NIDCR and the NIDDK, NIH.
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