The Journal of Immunology, Vol 157, Issue 7 2900-2908, Copyright © 1996 by American Association of Immunologists

ARTICLES

Requirements for induction of vitamin D-mediated gene regulation in normal human B lymphocytes

JW Morgan, DM Morgan, SR Lasky, D Ford, N Kouttab and AL Maizel
Department of Pathology, Roger Williams Medical Center, Brown University, Providence, RI 02908, USA. John_Morgan@brown.edu

Mature human lymphocytes are unique targets of 1 alpha,25- dihydroxyvitamin D3 (1 alpha,25(OH)2D3) in that vitamin D receptors (VDR) are not constitutively expressed, and specific cellular activation signals are required for both the up-regulation of VDR and establishment of reactivity to the lipophilic ligand. Treatment of B lymphocytes with the cytokine IL-4 (IL-4), in the absence of prior activation, induces a weak up-regulation of VDR expression but fails to generate vitamin D-responsive element (VDRE)-reactive nuclear protein complexes or to initiate the genomic transcription of 25-hydroxyvitamin D3 24-hydroxylase. Stimulation of B lymphocytes by either ligation of CD40 Ag or cross-linking the Ig receptor is also insufficient to render B lymphocytes responsive to 1 alpha,25(OH)2D3. However, this apparent lack of response to the secosterol can be overcome by stimulation of B lymphocytes with a combination of these cellular activation signals, which are sufficient to lead to G1 cell cycle progression. In the presence of 1 alpha,25(OH)2D3, cellular activation associated with stimulation of such a progression appears to be sufficient for the up- regulation of VDR message and protein and necessary for the establishment of VDRE binding complexes and the induction of 24- hydroxylase message. Furthermore, biologic functions are modulated, in that the hormone inhibits proliferation in a subset of the activated B cells. These observations suggest that reactivity to 1 alpha,25(OH)2D3 is tightly regulated in B lymphocytes, requiring specific signals for its initiation.

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