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J. Biol. Chem., Vol. 277, Issue 27, 24243-24251, July 5, 2002

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Novel Mode of Interference with Nuclear Factor of Activated T-cells Regulation in T-cells by the Bacterial Metabolite n-Butyrate^*

Christos Diakos, Eva E. Prieschl^§, Marcus Säemann, Veronica Novotny^§, Georg Böhmig^¶, Robert Csonga^§, Thomas Baumruker^§, and Gerhard J. Zlabinger

From the  Institute of Immunology, University of Vienna, Borschkegasse 8a, A-1090 Vienna, the ^§ Department of Allergic Diseases, Novartis Research Institute, Brunnerstrasse 53, A-1235 Vienna, and the ^¶ Department of Internal Medicine III, Division of Nephrology, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria

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 B 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.

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