Helicobacter pylori induces miR-155 in T cells in a cAMP-Foxp3-dependent manner.
Amongst the most severe clinical outcomes of life-long infections with Helicobacter pylori is the development of peptic ulcers and gastric adenocarcinoma--diseases often associated with an increase of regulatory T cells. Understanding H. pylori-driven regulation of T cells is therefore of crucial clinical importance. Several studies have defined mammalian microRNAs as key regulators of the immune system and of carcinogenic processes. Hence, we aimed here to identify H. pylori-regulated miRNAs, mainly in human T cells. MicroRNA profiling of non-infected and infected human T cells revealed H. pylori infection triggers miR-155 expression in vitro and in vivo. By using single and double H. pylori mutants and the corresponding purified enzymes, the bacterial vacuolating toxin A (VacA) and gamma-glutamyl transpeptidase (GGT) plus lipopolysaccharide (LPS) tested positive for their ability to regulate miR-155 and Foxp3 expression in human lymphocytes; the latter being considered as the master regulator and marker of regulatory T cells. RNAi-mediated knockdown (KD) of the Foxp3 transcription factor in T cells abolished miR-155 expression. Using adenylate cyclase inhibitors, the miR-155 induction cascade was shown to be dependent on the second messenger cyclic adenosine monophosphate (cAMP). Furthermore, we found that miR-155 directly targets the protein kinase A inhibitor alpha (PKIalpha) mRNA in its 3'UTR, indicative of a positive feedback mechanism on the cAMP pathway. Taken together, our study describes, in the context of an H. pylori infection, a direct link between Foxp3 and miR-155 in human T cells and highlights the significance of cAMP in this miR-155 induction cascade.
Fassi Fehri
Lina
L
Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany.
Koch
Manuel
M
Belogolova
Elena
E
Khalil
Hany
H
Bolz
Christian
C
Kalali
Behnam
B
Mollenkopf
Hans J
HJ
Beigier-Bompadre
Macarena
M
Karlas
Alexander
A
Schneider
Thomas
T
Churin
Yuri
Y
Gerhard
Markus
M
Meyer
Thomas F
TF
D020413:3' Untranslated Regions; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008070:Lipopolysaccharides / Q000737:chemistry; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D013601:T-Lymphocytes / Q000378:metabolism* / Q000382:microbiology*
D020413:3' Untranslated Regions; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D008070:Lipopolysaccharides; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D000242:Cyclic AMP