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NF-kappaB mediated transcriptional repression of acid modifying hormone gastrin.

ABSTRACT: Helicobacter pylori is a major pathogen associated with the development of gastroduodenal diseases. It has been reported that H. pylori induced pro-inflammatory cytokine IL1B is one of the various modulators of acid secretion in the gut. Earlier we reported that IL1B-activated NFkB down-regulates gastrin, the major hormonal regulator of acid secretion. In this study, the probable pathway by which IL1B induces NFkB and affects gastrin expression has been elucidated. IL1B-treated AGS cells showed nine-fold activation of MyD88 followed by phosphorylation of TAK1 within 15 min of IL1B treatment. Furthermore, it was observed that activated TAK1 significantly up-regulates the NFkB subunits p50 and p65. Ectopic expression of NFkB p65 in AGS cells resulted in about nine-fold transcriptional repression of gastrin both in the presence and absence of IL1B. The S536A mutant of NFkB p65 is significantly less effective in repressing gastrin. These observations show that a functional NFkB p65 is important for IL1B-mediated repression of gastrin. ChIP assays revealed the presence of HDAC1 and NFkB p65 along with NCoR on the gastrin promoter. Thus, the study provides mechanistic insight into the IL1B-mediated gastrin repression via NFkB.

SUBMITTER: Datta De D

PROVIDER: S-EPMC3751843 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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NF-kappaB mediated transcriptional repression of acid modifying hormone gastrin.

Datta De Dipanjana D Datta Arindam A Bhattacharjya Sumana S Roychoudhury Susanta S

PloS one 20130823 8

Helicobacter pylori is a major pathogen associated with the development of gastroduodenal diseases. It has been reported that H. pylori induced pro-inflammatory cytokine IL1B is one of the various modulators of acid secretion in the gut. Earlier we reported that IL1B-activated NFkB down-regulates gastrin, the major hormonal regulator of acid secretion. In this study, the probable pathway by which IL1B induces NFkB and affects gastrin expression has been elucidated. IL1B-treated AGS cells showed ...[more]

PMID: 24009751

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Project description:Acting via the glucocorticoid receptor (GR), glucocorticoids exert potent anti-inflammatory effects partly by repressing inflammatory gene transcription occurring via factors such as NF-kappaB. In the present study, the synthetic glucocorticoid, dexamethasone, induces expression of MKP-1 (mitogen-activated protein kinase (MAPK) phosphatase-1) in human bronchial epithelial (BEAS-2B) and pulmonary (A549) cells. This correlates with reduced TNFalpha-stimulated p38 MAPK phosphorylation. Since NF-kappaB-dependent transcription and IL-8 protein, mRNA, and unspliced RNA (a surrogate of transcription rate) are sensitive to p38 MAPK inhibitors (SB203580 and SB239063), we explored the role of MKP-1 in repression of these outputs. Repression of TNFalpha-induced p38 MAPK phosphorylation, NF-kappaB-dependent transcription, and IL-8 expression by dexamethasone are sensitive to transcriptional or translational inhibitors. This indicates a role for de novo gene synthesis. Adenoviral expression of MKP-1 profoundly reduces p38 MAPK phosphorylation and IL-8 expression. Similarly, NF-kappaB-dependent transcription is significantly reduced to levels consistent with maximal p38 MAPK inhibition. Thus, MKP-1 attenuates TNFalpha-dependent activation of p38 MAPK, induction of IL-8 expression, and NF-kappaB-dependent transcription. Small interfering RNA knockdown of dexamethasone-induced MKP-1 expression partially reverses the repression of TNFalpha-activated p38 MAPK, demonstrating that MKP-1 participates in the dexamethasone-dependent repression of this pathway. In the presence of MKK6 (MAPK kinase 6), a p38 MAPK activator, dexamethasone dramatically represses TNFalpha-induced NF-kappaB-dependent transcription, and this is significantly reversed by MKP-1-targeting small interfering RNA. This reveals an important and novel role for transcriptional activation (transactivation) of MKP-1 in the repression of NF-kappaB-dependent transcription by glucocorticoids. We conclude that GR transactivation is essential to the anti-inflammatory properties of GR ligands.

Project description:BACKGROUND: Exposure of macrophages to bacterial products such as lipopolysaccharide (LPS) results in activation of the NF-kappaB transcription factor, which orchestrates a gene expression programme that underpins the macrophage-dependent immune response. These changes include the induction or repression of a wide range of genes that regulate inflammation, cell proliferation, migration and cell survival. This process is tightly regulated and loss of control is associated with conditions such as septic shock, inflammatory diseases and cancer. To study this response, it is important to have in vitro model systems that reflect the behaviour of cells in vivo. In addition, it is necessary to understand the natural differences that can occur between individuals. In this report, we have investigated and compared the LPS response in macrophage derived cell lines and peripheral blood mononuclear cell (PBMC) derived macrophages. RESULTS: Gene expression profiles were determined following LPS treatment of THP-1 cells for 1 and 4 hours. LPS significantly induced or repressed 72 out of 465 genes selected as being known or putative NF-kappaB target genes, which exhibited 4 temporal patterns of expression. Results for 34 of these genes, including several genes not previously identified as LPS target genes, were validated using real time PCR. A high correlation between microarray and real time PCR data was found. Significantly, the LPS induced expression profile of THP-1 cells, as determined using real time PCR, was found to be very similar to that of human PBMC derived macrophages. Interestingly, some differences were observed in the LPS response between the two donor PBMC macrophage populations. Surprisingly, we found that the LPS response in U937 cells was dramatically different to both THP-1 and PBMC derived macrophages. CONCLUSION: This study revealed a dynamic and diverse transcriptional response to LPS in macrophages, involving both the induction and repression of gene expression in a time dependent manner. Moreover, we demonstrated that the LPS induced transcriptional response in the THP-1 cell line is very similar to primary PBMC derived macrophages. Therefore, THP-1 cells represent a good model system for studying the mechanisms of LPS and NF-kappaB dependent gene expression.

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NF-kappaB mediated transcriptional repression of acid modifying hormone gastrin.

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NF-kappaB mediated transcriptional repression of acid modifying hormone gastrin.

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