Article

Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production

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Abstract

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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Change history

  • Corrected online 06 April 2009

    In the version of this article initially published, the labeling in (Figure 4) was incorrect. In panel (b), the cells in the left two FACS plots are shown based on their size (FSC, y axis) and CD11b expression (x axis), and the cells in the right two FACS plots are shown based on their F4/80 expression (y axis) and GR1 expression (x axis). In panel (c), the curves should start at 1 h. In panel (d), the text labeling the y axis should read “in vitro,” not “in vivo.” The errors have been corrected in the HTML and PDF versions of this article.

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Acknowledgements

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.

Author information

Author notes

    • Krisztián Németh
    • , Asada Leelahavanichkul
    • , Robert A Star
    •  & Éva Mezey

    These authors contributed equally to this work.

Affiliations

  1. National Institute of Dental and Craniofacial Research (NIDCR), Craniofacial and Skeletal Diseases Branch, 9000 Rockville Pike, Bethesda, Maryland, 20892, USA

    • Krisztián Németh
    • , Balázs Mayer
    • , Alissa Parmelee
    • , Pamela G Robey
    • , Kantima Leelahavanichkul
    •  & Éva Mezey
  2. National Institute of Diabetes and Digestive Kidney Diseases (NIDDK), Renal Diagnostics and Therapeutics Unit, 9000 Rockville Pike, Bethesda, Maryland, 20892, USA

    • Asada Leelahavanichkul
    • , Peter S T Yuen
    • , Kent Doi
    • , Xuzhen Hu
    •  & Robert A Star
  3. National Cancer Institute (NCI), Experimental Immunology Branch, US National Institutes of Health (NIH), 9000 Rockville Pike, Bethesda, Maryland, 20892, USA.

    • Ivett Jelinek
  4. Department of Genetics, University of North Carolina, 4341 Medical Biomolecular Research Building, Chapel Hill, North Carolina 27599, USA.

    • Beverly H Koller
  5. Department of Pharmacology and Toxicology, East Carolina University, Greenville, North Carolina 27858, USA.

    • Jared M Brown

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Correspondence to Éva Mezey.

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    Supplementary Figs. 1–5, Supplementary Table 1 and Suppmenentary Methods