title: Novel mode of interference with nuclear factor of activated T-cells regulation in T-cells by the bacterial metabolite n-butyrate.
abstract: The transcription factor nuclear factor of activated T-cells (NF-AT) plays an essential role in the activation of many early immune response genes. A dynamic equilibrium between calcineurin and cellular kinases controls its phosphorylation and thus regulates its activity by determining its subcellular localization. Here, we demonstrate that T-cell activation in the presence of the bacterial metabolite n-butyrate, which leads to inhibition of interleukin-2 transcription, is characterized by the maintenance of the activity of counter-regulatory kinases glycogen synthase kinase 3 and protein kinase A as well as persistence of intracellular cAMP levels, whereas calcium response and mitogen-activated protein kinase activation were indistinguishable from cells stimulated in the absence of n-butyrate. Nuclear binding of NF-AT was decreased but other transcription factors implicated in interleukin-2 expression such as AP1 and nuclear factor kappaB were unaffected. The effect on NF-AT binding appeared to be the result of increased nuclear export because the export inhibitor leptomycin B completely restored nuclear binding of NF-AT. We, therefore, provide first evidence for interference with NF-AT regulation alternative to the currently understood inhibition of nuclear import. This mechanism might represent a bacterial strategy to subvert host defense, which could be of particular clinical importance in the gastrointestinal tract where high amounts of n-butyrate are physiologically present.
authors: Institute of Immunology, University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors: Christos
authors: C
authors: Diakos
authors: Eva E
authors: EE
authors: Prieschl
authors: Marcus
authors: M
authors: Saemann
authors: Veronica
authors: V
authors: Novotny
authors: Georg
authors: G
authors: Bohmig
authors: Robert
authors: R
authors: Csonga
authors: Thomas
authors: T
authors: Baumruker
authors: Gerhard J
authors: GJ
authors: Zlabinger
mesh_terms: D002087:Butyrates / Q000494:pharmacology*; D020013:Calcium Signaling / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D002087:Butyrates; D004268:DNA-Binding Proteins; D007376:Interleukin-2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D000242:Cyclic AMP; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)