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
