Coregulation and modulation of NF B-related genes in celiac disease: uncovered aspects of gut mucosal inflammation

Abstract

It is known that the NFκB route is constitutively upregulated in celiac disease (CD), an immune-mediated disorder of the gut caused by intolerance to ingested gluten. Our aim was to scrutinize the expression patterns of several of the most biologically relevant components of the NFκB route in intestinal biopsies from active and treated patients and after in vitro gliadin challenge, and to assess normalization of the expression using an inhibitor of the MALT1 paracaspase. The expression of 93 NFκB genes was measured by RT-PCR in a set of uncultured active and treated CD and control biopsies, and in cultured biopsy series challenged with gliadin, the NFκB modulator, both compounds and none. Methylation of eight genes involved in NFκB signaling was analyzed by conventional pyrosequencing. Groups were compared and Pearson's correlation matrixes were constructed to check for coexpression and co-methylation. Our results confirm the upregulation of the NFκB pathway and show that constitutively altered genes usually belong to the core of the pathway and have central roles, whereas genes overexpressed only in active CD are more peripheral. Additionally, this is the first work to detect methylation level changes in celiac intestinal mucosa. Coexpression is very common in controls, whereas gliadin challenge and especially chronic inflammation present in untreated CD result in the disruption of the regulatory equilibrium. In contrast, co-methylation occurs more often in active CD. Importantly, NFκB modulation partially restores coregulation, opening the door to future therapeutic possibilities and targets.

A long noncoding RNA associated with susceptibility to celiac disease

“…1D and fig. S5, D and E), consistent with the observation that NF-κB is constitutively active in the mucosa of patients with CeD (4). The lack of Myd88 did not affect Il18rap induction but does affect IL-12 (Fig.…”

“…Long noncoding RNAs (lncRNAs) represent a large portion of noncoding regions across the genome (1); however, the link between the GWAS phenotype–related loci on lncRNA expression or function—and the implications for disease—remain uncharacterized (2, 3). Celiac disease (CeD) is a chronic, immune-mediated intestinal disorder that is caused by intolerance to ingested gluten and develops in genetically susceptible individuals (4, 5). Recent studies have revealed 39 non– human lymphocyte antigen regions associated with a risk of CeD development, including many in noncoding regions (6–8).…”

The genetics of celiac disease: A comprehensive review of clinical implications

“…Fern andezJim enez et al [121] studied the expression in intestinal biopsies of 93 NFkB-related genes and confirmed the activation of a considerable fraction of those genes in CD. Notoriously, genes of the core of the pathway were increased in the group of constitutively altered genes (independently of the patients were following a GFD or not), in contrast to the increased number of more peripheral genes observed in patients with active disease.…”

Identification of novel long non-coding RNAs deregulated in hepatocellular carcinoma using RNA-sequencing

“…Correlation between the expression of a subset of differentially expressed long non-coding genes and their closest genes was performed as previously described using Pearson correlations [54]. …”