期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 308, 期 1, 页码 L86-L95出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00283.2014
关键词
alveolar macrophage; bone marrow transplantation; microRNA-29b; prostaglandin; transforming growth factor-beta
资金
- NIH [R56AI065543, HL115618, U01 HL098961, T32AI007413, T32 HL07749, HL094657]
- American Heart Association
- Miller Fund Award for Innovative Immunology Research
- Biomedical Laboratory Sciences Research & Development Service [1 I01 BX001389]
- Department of Veterans Affairs
- [AI117229]
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 E-2 (PGE(2)) in promoting impaired alveolar macrophage (AM) responses. However, mechanisms driving COX-2 overexpression remained elusive. Previously, transforming growth factor-beta (TGF-beta) 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-beta 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 PGE(2), 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.
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