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

• Published in: Human molecular genetics 2014-03, Vol.23 (5), p.1298-1310
• Main Authors: Fernandez-Jimenez, Nora, Castellanos-Rubio, Ainara, Plaza-Izurieta, Leticia, Irastorza, Iñaki, Elcoroaristizabal, Xabier, Jauregi-Miguel, Amaia, Lopez-Euba, Tamara, Tutau, Carlos, de Pancorbo, Marian M, Vitoria, Juan Carlos, Bilbao, Jose Ramon
• Format: Article
• Language: English
• Subjects: Celiac Disease - genetics; Celiac Disease - metabolism; Cluster Analysis; DNA Methylation; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Humans; Inflammation - genetics; Inflammation - metabolism; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; NF-kappa B - metabolism; Promoter Regions, Genetic; Signal Transduction
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddt520

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.