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-) reprogram macrophages by releasing prostaglandin E 2 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. © 2008 Nature Publishing GroupCorrespondence should be addressed to E.M. (E-mail: mezeye@mail.nih.gov).. 6 These authors contributed equally to this work. AUTHOR CONTRIBUTIONS K.N., A.L., P.S.T.Y., R.A.S. and E.M. formulated the basic hypotheses and experimental design; K.N., A.L., E.M., P.S.T.Y. and R.A.S. collected and evaluated data on survival and organ injury; K.N. and A.L. performed the in vivo experiments; A.L., P.S.T.Y., A.P., K.D., K.L. and X.H. assisted in the in vivo experiments and histology; P.G.R. consulted on BMSC biology; K.N. formulated the molecular mechanism hypothesis and designed and performed in vitro and ex vivo assays; B.H.K. helped to test the involvement of the prostaglandin receptors; J.M.B. and B.M. contributed to testing the involvement of COX2; B.M. performed the measurements for tissue peroxidase; I.J. performed FACS experiments; E.M. wrote the initial manuscript and prepared the figures; all of the authors edited the manuscript.Note: Supplementary information is available on the Nature Medicine website. In the last few years, it has been discovered that BMSCs are potent modulators of immune responses 2-5 . We wondered whether such cells could bring the immune response back into balance, thus attenuating the underlying pathophysiology that eventually leads to severe sepsis, septic shock and death 6,7 . NIH Public AccessAs a model of sepsis, we chose cecal ligation and puncture (CLP), a procedure that has been used for more than two decades 8 . This mouse model closely resembles the human disease: it has a focal origin (cecum), is caused by multiple intestinal organisms, and results in septicemia with release of bacterial toxins into the circulation. With no treatment, the ma...
The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16␣-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7␣-hydroxylase (Cyp7a1) and the Na ؉ -independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.
BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance. Importantly, our results also demonstrate that the BRCA1-PALB2 interaction dictates the choice between HR and SSA. These studies establish functional and mutational landscapes of BRCA1 for HDR and therapy resistance, while revealing novel insights into BRCA1 regulatory mechanisms and HDR pathway choice.
N-methyl-D-aspartate receptors (NMDARs) represent a subclass of glutamate receptors that play a critical role in neuronal development and physiology. We report here the generation of mice expressing only 5% of normal levels of the essential NMDAR1 (NR1) subunit. Unlike NR1 null mice, these mice survive to adulthood and display behavioral abnormalities, including increased motor activity and stereotypy and deficits in social and sexual interactions. These behavioral alterations are similar to those observed in pharmacologically induced animal models of schizophrenia and can be ameliorated by treatment with haloperidol or clozapine, antipsychotic drugs that antagonize dopaminergic and serotonergic receptors. These findings support a model in which reduced NMDA receptor activity results in schizophrenic-like behavior and reveals how pharmacological manipulation of monoaminergic pathways can affect this phenotype.
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