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Exp Clin Endocrinol Diabetes 2004; 112(10): 595-600
DOI: 10.1055/s-2004-830405
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Vitamin B6 Modulates Glucocorticoid-Dependent Gene Transcription in a Promoter- and Cell Type-Specific Manner

C. M. Bamberger1 , T. Else1 , I. Ellebrecht1 , K. Milde-Langosch2 , D. Pankoke1 , F. U. Beil1 , A.-M. Bamberger2
  • 1Department of Medicine I, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  • 2Institute of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
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Publication History

Received: October 30, 2003 First decision: January 22, 2004

Accepted: May 3, 2004

Publication Date:
02 December 2004 (online)

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Abstract

Due to their immunosuppressive effects, glucocorticoids (GC) are widely used in the treatment of inflammatory and autoimmune states. However, long-term GC treatment is associated with severe side effects. To increase the ratio of wanted and unwanted GC effects, is, therefore, a desirable goal, which could be achieved by either developing new “dissociating” GC or by combining conventional GC therapy with substances that selectively interfere with glucocorticoid receptor (GR) function. Vitamin B6 was previously shown to inhibit GR transactivation in non-immune cells. In the present study, we tested whether vitamin B6 would also interfere with GR function in immune cells and/or with transrepression in non-immune cells. Normal human lymphocytes and Jurkat T lymphoma cells were transfected with luciferase reporter constructs under the control of the interleukin-2 (IL-2) and the leukemia inhibitory factor (LIF) promoter, respectively. Cells were stimulated with phorbol ester, ionomycin, and different concentrations of dexamethasone, either in the absence (a vitamin B6-free medium was especially prepared for this study) or presence of vitamin B6. Both promoters were strongly induced in response to phorbol ester and ionomycin. Dexamethasone inhibited this effect in a dose-dependent manner both in the presence and absence of vitamin B6. Similar results were obtained at the protein level (IL-2- and LIF-specific ELISAs). Induction of a glucocorticoid response element (GRE)-driven promoter construct by dexamethasone in lymphoid cells was only marginally reduced by vitamin B6. In contrast, GR-mediated transactivation was strongly inhibited by vitamin B6 in HeLa cells, while GR-mediated transrepression of a matrix metalloproteinase 9 (MMP9) promoter construct was not affected. Our data indicate that vitamin B6 does not interfere with GC action in immune cells (wanted GC effects) while selectively inhibiting GR-dependent transactivation in non-immune cells (unwanted GC effects). Combination of GC treatment with supraphysiological doses of vitamin B6 may, thus, reduce the side effects of this type of immunosuppressive therapy, provided that the observed effects can be reproduced at subtoxic vitamin B6 concentrations in vivo.

Key words

Glucocorticoid receptor - vitamin B6 - transactivation - transrepression

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M.D., Professor of Medicine and Endocrinology Christoph M. Bamberger

Department of Medicine I
University Hospital Hamburg-Eppendorf

Martinistraße 52

20246 Hamburg

Germany

Phone: + 4940428033907

Fax: + 49 4 04 28 03 92 52

Email: bamberger@uke.uni-hamburg.de

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