Transforming growth factor-β induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation
| Autor: | Jeanette P. Brown, Yasmina Laouar, Gregory A. Yanik, Christine M. Freeman, Racquel Domingo-Gonzalez, Steven K. Huang, Carol A. Wilke, Jeffrey L. Curtis, Bethany B. Moore |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Pulmonary and Respiratory Medicine
Adult Male Methyltransferase Physiology medicine.medical_treatment Hematopoietic stem cell transplantation Biology Dinoprostone Mice Downregulation and upregulation Transforming Growth Factor beta Physiology (medical) microRNA Macrophages Alveolar medicine Animals Humans DNA (Cytosine-5-)-Methyltransferases Prostaglandin E2 Bone Marrow Transplantation Hematopoietic Stem Cell Transplantation Cell Biology Transfection Articles DNA Methylation Middle Aged Allografts MicroRNAs surgical procedures operative Cyclooxygenase 2 Immunology Cancer research Alveolar macrophage Female Transforming growth factor medicine.drug Signal Transduction |
| Popis: | Hematopoietic stem cell transplantation (HSCT) is complicated by pulmonary infections that manifest posttransplantation. Despite engraftment, susceptibility to infections persists long after reconstitution. Previous work using a murine bone marrow transplant (BMT) model implicated increased cyclooxygenase-2 (COX-2) and prostaglandin E2(PGE2) in promoting impaired alveolar macrophage (AM) responses. However, mechanisms driving COX-2 overexpression remained elusive. Previously, transforming growth factor-β (TGF-β) signaling after BMT was shown to promote hypomethylation of the COX-2 gene. Here, we provide mechanistic insight into how this occurs and show that TGF-β induces microRNA (miR)-29b while decreasing DNA methyltransferases (DNMT)1, DNMT3a, and DNMT3b in AMs after BMT. De novo DNMT3a and DNMT3b were decreased upon transient transfection of miR-29b, resulting in decreased methylation of the COX-2 promoter and induction of COX-2. As a consequence, miR-29b-driven upregulation of COX-2 promoted AM dysfunction, and transfection of BMT AMs with a miR-29b inhibitor rescued the bacterial-killing defect. MiR-29b-mediated defects in BMT AMs were dependent on increased levels of PGE2, as miR-29b-transfected AMs treated with a novel E prostanoid receptor 2 antagonist abrogated the impaired bacterial killing. We also demonstrate that patients that have undergone HSCT exhibit increased miR-29b; thus these studies highlight miR-29b in driving defective AM responses and identify this miRNA as a potential therapeutic target. |
| Databáze: | OpenAIRE |
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