Requirements for induction of vitamin D-mediated gene regulation in normal human B lymphocytes.
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.
Morgan
J W
JW
Department of Pathology, Roger Williams Medical Center, Brown University, Providence, RI 02908, USA. John_Morgan@brown.edu
Morgan
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Lasky
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Ford
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Kouttab
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Maizel
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D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D001483:Base Sequence; D019013:CD40 Antigens / Q000276:immunology; D002117:Calcitriol / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009000:Monocytes; D009687:Nuclear Proteins / Q000378:metabolism; D014066:Palatine Tonsil / Q000276:immunology; D018167:Receptors, Calcitriol / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D012045:Regulatory Sequences, Nucleic Acid; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
D019013:CD40 Antigens; D007376:Interleukin-2; D009687:Nuclear Proteins; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D015847:Interleukin-4; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol