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, 294 (17), 6785-6795

The Proinflammatory Cytokine TNFα Induces DNA Demethylation-Dependent and -Independent Activation of interleukin-32 Expression

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The Proinflammatory Cytokine TNFα Induces DNA Demethylation-Dependent and -Independent Activation of interleukin-32 Expression

Zuodong Zhao et al. J Biol Chem.

Abstract

IL-32 is a cytokine involved in proinflammatory immune responses to bacterial and viral infections. However, the role of epigenetic events in the regulation of IL-32 gene expression is understudied. Here we show that IL-32 is repressed by DNA methylation in HEK293 cells. Using ChIP sequencing, locus-specific methylation analysis, CRISPR/Cas9-mediated genome editing, and RT-qPCR (quantitative RT-PCR) and immunoblot assays, we found that short-term treatment (a few hours) with the proinflammatory cytokine tumor necrosis factor α (TNFα) activates IL-32 in a DNA demethylation-independent manner. In contrast, prolonged TNFα treatment (several days) induced DNA demethylation at the promoter and a CpG island in the IL-32 gene in a TET (ten-eleven translocation) family enzyme- and NF-κB-dependent manner. Notably, the hypomethylation status of transcriptional regulatory elements in IL-32 was maintained for a long time (several weeks), causing elevated IL-32 expression even in the absence of TNFα. Considering that IL-32 can, in turn, induce TNFα expression, we speculate that such feedforward events may contribute to the transition from an acute inflammatory response to chronic inflammation.

Keywords: DNA demethylation; DNA methylation; IL-32; NF-κB; TNFα; epigenetics; gene activation; gene regulation; inflammation; transcription; tumor necrosis factor (TNF).

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article

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