title: Dysregulated expression of miR-146a contributes to age-related dysfunction of macrophages.
abstract: Age-associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR-146a, which negatively regulated the expression of IL-1β and IL-6, was highly expressed in aged mice. However, there was a lack of response to the stimulation of lipopolysaccharide (LPS) and proinflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR-146a involving down-regulation of inflammation factors was interrupted in aged mice. Aberrant NF-κB binding to the miR-146a promoter was demonstrated to be associated with the abnormal expression of miR-146a in aged mice. The DNA methyltransferase inhibitor (5-aza-2-deoxycytidine) and the histone deacetylase inhibitor [trichostatin A (TSA)] both significantly up-regulated miR-146a transcriptional activation by altering the DNA-binding activity of NF-κB in macrophages isolated from aged mice, which suggests that DNA methylation and histone acetylation are involved in the suppression of age-dependent miR-146a expression. Additionally, high levels of histone deacetylase (HDACs) expressions contributed to the inhibition of miR-146a expression in LPS-stimulated macrophages from aged mice in vitro. While the suppression of HDACs activities by TSA could improve LPS-induced inflammatory responses owing to up-regulation of miR-146a expression in macrophages from aged mice. These data indicate that the dysregulated expression of miR-146a results in the age-associated dysfunction of macrophages, and miR-146a may be a good target for the treatment of age-related inflammatory diseases.
authors: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors: Minghong
authors: M
authors: Jiang
authors: Yang
authors: Y
authors: Xiang
authors: Dongsheng
authors: D
authors: Wang
authors: Jing
authors: J
authors: Gao
authors: Dan
authors: D
authors: Liu
authors: Yanxin
authors: Y
authors: Liu
authors: Shilian
authors: S
authors: Liu
authors: Dexian
authors: D
authors: Zheng
mesh_terms: D000107:Acetylation; D000375:Aging / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics* / Q000276:immunology
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D004248:DNA (Cytosine-5-)-Methyltransferases; D006655:Histone Deacetylases