Methylation-Dependent Gene Silencing Induced by Interleukin 1β via Nitric Oxide Production

Abstract

Interleukin (IL)-1β is a pleiotropic cytokine implicated in a variety of activities, including damage of insulin-producing cells, brain injury, or neuromodulatory responses. Many of these effects are mediated by nitric oxide (NO) produced by the induction of NO synthase (iNOS) expression. We report here that IL-1β provokes a marked repression of genes, such as fragile X mental retardation 1 (FMR1) and hypoxanthine phosphoribosyltransferase (HPRT), having a CpG island in their promoter region. This effect can be fully prevented by iNOS inhibitors and is dependent on DNA methylation. NO donors also cause FMR1 and HPRT gene silencing. NO-induced methylation of FMR1 CpG island can be reverted by demethylating agents which, in turn, produce the recovery of gene expression. The effects of IL-1β and NO appear to be exerted through activation of DNA methyltransferase (DNA MeTase). Although exposure of the cells to NO does not increase DNA MeTase gene expression, the activity of the enzyme selectively increases when NO is applied directly on a nuclear protein extract. These findings reveal a previously unknown effect of IL-1β and NO on gene expression, and demonstrate a novel pathway for gene silencing based on activation of DNA MeTase by NO and acute modification of CpG island methylation.

Promoter hypermethylation ofCDH1,FHIT,MTAPandPLAGL1in gastric adenocarcinoma in individuals from Northern Brazil

“…In our study, a higher hypermethylation frequency of CpG islands was found in H pylori infected samples, confirming findings from studies by El-Omar et al [42,43] and Hmadcha et al [44] . El-Omar et al [42,43] reported that interleukin-1β polymorphism led to an upregulation of interleukin-1β with H pylori infection and was associated with increased risk of GC.…”

Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin

“…Currently, it is widely accepted that chronic inflammation promotes tumor initiation and progression through the induction of various genetic and epigenetic alterations. For example, inflammation enhances the production of reactive oxygen species, up-regulates the expression of the enzyme that induces nucleotide alterations (9), and modulates the activity of DNA methyltransferases (10). Interestingly, inflammation also has been shown to deregulate self-renewal and differentiation of hematopoietic stem cells (11).…”

Interleukin-1β increases the risk of gastric cancer through induction of aberrant DNA methylation in a mouse model

“…Proinflammatory cytokine IL-1β has a significant role in gastric carcinogenesis (16,17,25). In the present study, IL-1R1 -/ -mice, which are unresponsive to IL-1β, were used to fully elucidate the specific role of IL-1β in linking gastric inflammation to DNA methylation induction.…”

“…It has been demonstrated that IL-1β may induce DNA methylation in vitro (16)(17)(18). This methylation-dependent gene silencing mechanism is via IL-1β activation of NO production (16,18).…”

“…This methylation-dependent gene silencing mechanism is via IL-1β activation of NO production (16,18). Thus, the present study used mice in which the interleukin 1 receptor type 1 (IL-1R1) was deleted in order to characterize the specific role of IL-1β in H. pylori-induced DNA methylation.…”