Role of Complex Epigenetic Switching in Tumor Necrosis Factor-α Upregulation in the Prefrontal Cortex of Suicide Subjects

摘要

Objective: Proinflammatory cytokines have recently received considerable attention for their role in suicidal behavior; however, how the expression of cytokine genes is regulated is not clearly known. The authors examined underlying mechanisms of critical cytokine gene tumor necrosis factor-alpha (TNF-? dysregulation in the brains of individuals who died by suicide.Method: TNF-?expression was examined in the dorsolateral prefrontal cortex of the postmortem brains of persons with and without major depressive disorder who died by suicide and of persons with major depressive disorder who died of causes other than suicide. The role of putative microRNAs targeting TNF-?and RNA-binding protein Hu antigen R (HuR) was tested with in vitro and in vivo approaches and by examining expression of transactivation response RNA binding protein (TRBP). Genetic influence on TNF-?expression was determined by expression quantitative trait loci analysis and by genotyping three singlenucleotide polymorphisms in the promoter region of the TNF-?gene. Promoter methylation of TNF-?was determined by using methylated DNA immunoprecipitation assay. Expression of miR-19a-3p and TNF-?was also determined in the peripheral blood mononuclear cells of 12 healthy control subjects and 12 currently depressed patients with severe suicidal ideation.Results: TNF-?expression was significantly higher in the dorsolateral prefrontal cortex of individuals who died by suicide, regardless of psychiatric diagnosis. Its expression level was also increased in individuals with major depressive disorder who died by causes other than suicide. On the other hand, expression of miR-19a-3p was upregulated specifically in individuals who died by suicide. In a preliminary observation, similar upregulation of TNF-?and miR-19a-3p was observed in the peripheral blood mononuclear cells of depressed patients with suicidal ideation. Despite its ability to directly target TNF-?in vitro, miR-19a-3p showed no interaction with TNF-?in the dorsolateral prefrontal cortex. HuR potentially stabilized TNF-?transcript, presumably by sequestering its 3' untranslated region from miR-19a-3p-mediated inhibition. Furthermore, decreased TRBP expression supported abnormality in the interaction between miR-19a-3p and TNF-? Additionally, TNF-?transcriptional upregulation was associated with promoter hypomethylation, whereas no genetic influence on altered TNF-?or miR-19a-3p expression was observed in individuals who died by suicide.Conclusions: The data in this study provide mechanistic insights into the dysregulation of the TNF-?gene in the brains of individuals who died by suicide, which could potentially be involved in suicidal behavior.