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Coregulation and modulation of NFκB-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.

SUBMITTER: Fernandez-Jimenez N

PROVIDER: S-EPMC3919015 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Fernandez-Jimenez Nora N Castellanos-Rubio Ainara A Plaza-Izurieta Leticia L Irastorza Iñaki I Elcoroaristizabal Xabier X Jauregi-Miguel Amaia A Lopez-Euba Tamara T Tutau Carlos C de Pancorbo Marian M MM Vitoria Juan Carlos JC Bilbao Jose Ramon JR

Human molecular genetics 20131024 5

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 NFκ ...[more]

PMID: 24163129

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Project description:ObjectiveAnkylosing spondylitis (AS) patients often present with microscopic signs of gut inflammation. We used proteomic techniques to identify the differentially expressed proteins (DEPs) in the colon tissues of patients with AS and patients with gut inflammation, and then used investigated the influence of NMRAL1 protein on inflammatory cytokines to explore its potential role in the pathogenesis of AS and gut inflammation.MethodsColonic mucosal tissues were collected from four different groups: healthy individuals (group A), patients with gut inflammation only (group B), patients with AS only (group C), and patients with AS combined with gut inflammation (group D). A total of 20 samples were processed for proteomic analysis, wherein proteins were extracted using SDT lysis, followed by separation via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The proteins were digested using the filter-aided sample preparation (FASP) method and then analyzed using a timsTOF Pro mass spectrometer. The resulting peptide data were used to identify differentially expressed proteins (DEPs) across the different groups. To further explore the inflammation-related function of NMRAL1 protein, the murine monocyte/macrophage cell line RAW264.7 was used. NMRAL1 mRNA expression levels were assessed via RT-qPCR, and inflammatory cytokine levels (TNF-α, IL-1β, IL-17 and IL-23) were measured using ELISA following NMRAL1 siRNA transfection in LPS-treated macrophages.ResultsWe collected colonic mucosa specimens from 20 patients, including groups A,B, C and D with 5 patients in each group. We established a database of DEPs and identified 107 (63 upregulated and 44 downregulated) between group B and group A, 78 (16 upregulated and 62 downregulated) between group D and group C, 45 (8 upregulated and 37 downregulated) between group D and group B, and 57 (33 upregulated and 24 downregulated) between group C and group A. Further analysis revealed that the NmrA-like family domain containing 1 (NMRAL1) protein was identified as a DEP specifically associated with group D. The results of in vitro results showed a significant decrease in NMRAL1 mRNA expression in LPS-treated cells (P<0.001), which was further reduced in NMRAL1 siRNA-transfected cells (P<0.0001), confirming successful transfection. ELISA results revealed that the levels of key inflammatory cytokines (TNF-α, IL-1β, IL-17 and IL-23) were significantly elevated in the LPS-treated model group (P<0.0001, P<0.001), but these levels were significantly decreased after NMRAL1 siRNA transfection (P<0.0001, P<0.01, P<0.05).ConclusionNMRAL1 is identified as a key differentially expressed protein in AS patients with gut inflammation. Knockdown of NMRAL1 significantly reduced the levels of inflammatory cytokines, suggesting its potential role in the pathogenesis of AS and gut inflammation, and as a possible therapeutic target.

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

Publications

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

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