期刊
HUMAN MOLECULAR GENETICS
卷 23, 期 5, 页码 1298-1310出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt520
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资金
- Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness [PI10/0310]
- Basque Departments of Health and Industry [SAN201111034, SAIO-PE08BF03]
- FPI grants from the Basque Department of Education, Universities and Research [BIF-2009-099, BIF-2010-189]
- Instituto de Salud Carlos III of the Spanish Ministry of Economy and Competitiveness
It is known that the NF kappa B 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 NF kappa B 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 NF kappa B 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 NF kappa B modulator, both compounds and none. Methylation of eight genes involved in NF kappa B 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 NF kappa B 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, NF kappa B modulation partially restores coregulation, opening the door to future therapeutic possibilities and targets.
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