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Helicobacter pylori induce miR-155 in T cells in a cAMP-Foxp3 dependant manner

ABSTRACT: The human pathogen Helicobacter pylori (Hp) colonizes the gastric epithelium as a unique niche in the stomach. Infections commonly occur in childhood and persist lifelong, leading in some cases to adenocarcinoma and MALT lymphoma. Several studies define mammalian microRNAs as key regulators of the immune system and of carcinogenesis processes. Here, we show Hp infection induces miR-155 expression in epithelial and hematopoietic cells in vitro and in vivo. This induction is mediated by at least two main bacterial virulence factors, the vacuolating toxin (VacA) and the gamma-glutamyl transpeptidase (GGT) in an LPS independent manner. Using adenylate cyclases agonists and inhibitor, we demonstrated that the miR-155 microRNA regulatory cascade in Hp infection involves the second messenger cyclic adenosine monophosphate (cAMP). Furthermore, the study showed that a knock-down of the Foxp3 transcription factor in T cells abolishes miR-155 expression. Together, these findings are the first demonstration of a direct interconnection between the regulatory T cell development factor Foxp3 and a microRNA. This study supports the link between Hp infection, regulation of cellular immunity, inflammation and cancer development.

ORGANISM(S): Mus musculus Rattus norvegicus Homo sapiens

PROVIDER: GSE18616 | GEO | 2010/12/22

SECONDARY ACCESSION(S): PRJNA121447

REPOSITORIES: GEO

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Project description:The cellular microRNA, miR-155 has been shown to be involved in lymphocyte activation and is expressed in EBV infected cells displaying type III latency gene expression but not type I latency gene expression. We show here that the elevated levels of miR-155 in type III latency cells is due to EBV gene expression and not epigenetic differences in cell lines tested and we show that expression in EBV infected cells requires a conserved AP-1 element in the miR-155 promoter. Gene expression analysis was carried out in a type I latency cell line transduced with a miR-155 expressing retrovirus. This analysis identified both miR-155 suppressed and induced cellular mRNAs and suggested that in addition to direct targeting of 3’ UTRs, miR-155 alters gene expression in part through the alteration of signal transduction pathways. 3’ UTR reporter analysis of predicted miR-155 target genes identified the transcriptional regulatory genes, BACH1, ZIC3, HIVEP2, CEBPB, ZNF652, ARID2, and SMAD5 as miR-155 targets. Western blot analysis of the most highly suppressed of these, BACH1, showed lower expression in cells transduced with a miR-155 retrovirus. Inspection of the promoters from genes regulated in EBV infected cells and in cells infected with a miR-155 retrovirus identified potential binding sequences for BACH1 and ZIC3. Together, these experiments suggest that the induction of miR-155 by EBV contributes to EBV mediated signaling in part through the modulation of transcriptional regulatory factors. Keywords: Differential expression of miR-155 vs cntl expressing cells The EBV positive Burkitt's lymphoma cell line, Akata was infected with a control (pEhyg-miRCntl) or a microRNA-155 expressing (pEhyg-miR-155) retrovirus. Duplicate infections with the control retrovirus and with the miR-155 retrovirus were carried out. Control and miR-155 infection pair 1 were run on an array as well as a dye swap. Control and miR-155 infection pair 2 were similarly run on an array as well as a second array containing a dye swap.

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Helicobacter pylori induce miR-155 in T cells in a cAMP-Foxp3 dependant manner

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