Normal myelopoiesis but abnormal T lymphocyte responses in vitamin D receptor knockout mice.
The vitamin D receptor (VDR) is a transcription factor that mediates the actions of its ligand, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], which can promote monocyte/macrophage differentiation and inhibit proliferation and cytokine production by activated T lymphocytes. In this study, VDR knockout (KO) mice were used to investigate the possible role of VDR in hematopoiesis. The relative number of red and white peripheral blood cells and the percentage of bone marrow macrophages did not differ between VDR KO and wild-type mice. 12-O-tetradecanoylphorbol-13-acetate, but not 1,25(OH)(2)D(3), induced differentiation of bone marrow-committed myeloid stem cells from VDR KO mice to monocytes/macrophages. Production of IL-18, a Th1-promoting cytokine, was reduced in macrophages from these mice. Antigen-stimulated spleen cells from VDR KO mice showed an impaired Th1 cell response and had decreased expression of STAT4, a Th1 cell transcription factor. These results demonstrate the absolute requirement of VDR for 1,25(OH)(2)D(3)-induced monocyte/macrophage differentiation but show that monocyte/macrophage differentiation can occur in the absence of this receptor. The observed reduction in Th1 population in these mutant mice may be explained by a loss of macrophage IL-18 production or a suppression of STAT4 expression by activated splenocytes.
O'Kelly
James
J
Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. okellyj@cshs.org
Hisatake
Junichi
J
Hisatake
Yasako
Y
Bishop
June
J
Norman
Anthony
A
Koeffler
H Phillip
HP
D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics* / Q000502:physiology*; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D018167:Receptors, Calcitriol; D002117:Calcitriol; D013755:Tetradecanoylphorbol Acetate