Decreased expression of vitamin D receptor may contribute to the hyperimmune status of patients with acquired aplastic anemia

Yu, Wei; Ge, Meili; Lu, Shihong; Shi, Jun; Feng, Sizhou; Li, Xingxin; Zhang, Jizhou; Wang, Min; Huang, Jinbo; Shao, Yijun; Huang, Zhendong; Zhang, Jing; Nie, Neng; Zheng, Yizhou

doi:10.1111/ejh.12628

Cited by 8 publications

(10 citation statements)

References 44 publications

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“…Calcitriol also inhibited the differentiation of Th17 and Th1 cells while increasing Th2 cells . Calcitriol decreased T‐bet mRNA levels in AA patient cells , supporting a shift from Th1 phenotype. Several autoimmune and hematological disorders share a similar cytokine profile of higher IFN‐ γ , IL‐10, IL‐6, and IL‐17, as observed across ITP, AIHA, Evan's syndrome, and CIN .…”

Section: Vitamin D Effects On Malignant Hematological Cellsmentioning

confidence: 83%

“…Surprisingly, untreated AA patients did not have altered circulating 25(OH)D 3 serum levels compared to healthy donors, but had significantly decreased VDR mRNA expression levels (31). Thus, VDR downregulation is hypothesized to contribute to the hyperimmune status of AA (31). On the contrary, in other autoimmune cytopenias and hematological disorders, specifically AIHA, ITP, Evan's syndrome, and CIN, VDR expression levels were higher in the disease state compared to normal donors (23).…”

Section: Vitamin D Receptormentioning

confidence: 90%

“…Similarly, calcitriol alters pro‐inflammatory cytokine production in PBMCs from AA patients. One study found that IFN‐ γ , TNF‐ α , IL‐10, IL‐17A, and TGF‐ β 1 levels were elevated in AA PBMCs, but calcitriol treatment significantly decreased the production of IFN‐ γ , TNF‐ α , and IL‐17A while increasing TGF‐ β 1 . Calcitriol also inhibited the differentiation of Th17 and Th1 cells while increasing Th2 cells .…”

Section: Vitamin D Effects On Malignant Hematological Cellsmentioning

confidence: 99%

“…One study found that IFN‐ γ , TNF‐ α , IL‐10, IL‐17A, and TGF‐ β 1 levels were elevated in AA PBMCs, but calcitriol treatment significantly decreased the production of IFN‐ γ , TNF‐ α , and IL‐17A while increasing TGF‐ β 1 . Calcitriol also inhibited the differentiation of Th17 and Th1 cells while increasing Th2 cells . Calcitriol decreased T‐bet mRNA levels in AA patient cells , supporting a shift from Th1 phenotype.…”

Section: Vitamin D Effects On Malignant Hematological Cellsmentioning

confidence: 99%

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Vitamin D in hematological disorders and malignancies

Kulling

Olson

et al. 2016

European J of Haematology

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Commonly known for its critical role in calcium homeostasis and bone mineralization, more recently vitamin D has been implicated in hematological cancer pathogenesis and shows promise as an anti-cancer therapy. Serum levels of 25(OH)D 3 , the precursor to the active form of vitamin D, calcitriol, are frequently lower in patients with hematological disease compared to healthy individuals. This often correlates with worse disease outcome. Furthermore, diseased cells typically highly express the vitamin D receptor, which is required for many of the anti-cancer effects observed in multiple in vivo and in vitro cancer models. In abnormal hematological cells, vitamin D supplementation promotes apoptosis, induces differentiation, inhibits proliferation, sensitizes tumor cells to other anti-cancer therapies, and reduces the production of pro-inflammatory cytokines. Although the dosage of vitamin D required to achieve these effects may induce hypercalcemia in humans, analogs and combinatorial treatments have been developed to circumvent this side effect. Vitamin D and its analogs are well tolerated in clinical trials, and thus, further investigation into the use of these agents in the clinic is warranted. Here, we review the current literature in this field.

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Section: Vitamin D Effects On Malignant Hematological Cellsmentioning

confidence: 83%

Section: Vitamin D Receptormentioning

confidence: 90%

Section: Vitamin D Effects On Malignant Hematological Cellsmentioning

confidence: 99%

Section: Vitamin D Effects On Malignant Hematological Cellsmentioning

confidence: 99%

See 2 more Smart Citations

Vitamin D in hematological disorders and malignancies

Kulling

Olson

et al. 2016

European J of Haematology

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“…For instance, the removal of bone debris through osteoclasts could be hampered since vitamin D controls osteoclast precursor monocyte migration [50]. On the other hand, in vitro studies demonstrated that vitamin D inhibits dendritic cell maturation and function as well as T cell proliferation and influences B cell responses, inhibiting proliferation and plasma cell differentiation [51–54]. An altered cytokine release by immune cells caused by a low vitamin D level could lead to a dysregulation of osteoclast activation and differentiation via associated immunoreceptors in osteoclasts [55].…”

Section: Discussionmentioning

confidence: 99%

Vitamin D deficiency in early implant failure: two case reports

et al. 2016

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An association between vitamin D deficiency and early dental implant failure is not properly verified, but its role in osteoimmunology is discussed. This article illustrates two case reports with vitamin D deficiency and early implant failure. Prior to implant placement, the first patient received crestal bone grafting with autologous material. Both patients received dental implants from different manufacturers in the molar region of the mandible. In the case of bone grafting in the first patient, all implants were placed in a two-stage procedure. All implants had to be removed within 15 days after implant placement. Vitamin D serum levels were measured: Both patients showed a vitamin D deficiency (serum vitamin D level <20 μg/l). After vitamin D supplementation, implant placement was successful in both patients. Prospective, randomized clinical trials must follow to affirm the relationship between vitamin D deficiency, osteoimmunology, and early implant failure.

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Calcitriol-mediated reduction in IFN-γ output in T cell large granular lymphocytic leukemia requires vitamin D receptor upregulation

Kulling

Olson

et al. 2018

The Journal of Steroid Biochemistry and Molecular Biology

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Constitutively activated STAT1 and elevated IFN-γ are both characteristic of T cell large granular lymphocytic leukemia (T-LGLL), a rare incurable leukemia with clonal expansion of cytotoxic T cells due to defective apoptosis. Interferon gamma (IFN-γ) is an inflammatory cytokine that correlates with worse progression and symptomology in multiple autoimmune diseases and cancers. In canonical IFN-γ-STAT1 signaling, IFN-γ activates STAT1, a transcription factor, via phosphorylation of tyrosine residue 701 (p-STAT1). p-STAT1 then promotes transcription of IFN-γ, creating a positive feedback loop. We previously found that calcitriol treatment of the TL-1 cell line, a model of T-LGLL, significantly decreased IFN-γ secretion and p-STAT1 while increasing the vitamin D receptor (VDR) protein. Here we further explore these observations. Using TL-1 cells, IFN-γ decreased starting at 4h following calcitriol treatment, with a reduction in the intracellular and secreted protein levels as well as the mRNA content. A similar reduction in IFN-γ transcript levels was observed in primary T-LGLL patient peripheral blood mononuclear cells (PBMCs). p-STAT1 inhibition followed a similar temporal pattern and VDR upregulation inversely correlated with IFN-γ levels. Using EB1089 and 25(OH)D, which have high or low affinity for VDR, respectively, we found that the decrease in IFN-γ correlated with the ability of EB1089, but not 25(OH)D, to upregulate VDR. However, both compounds inhibited p-STAT1; thus the reduction of p-STAT1 is not solely responsible for IFN-γ inhibition. Conversely, cells treated with VDR siRNA exhibited decreased basal IFN-γ production upon VDR knockdown in a dose-dependent manner. Calcitriol treatment upregulated VDR and decreased IFN-γ regardless of initial VDR knockdown efficiency, strengthening the connection between VDR upregulation and IFN-γ reduction. Our findings suggest multiple opportunities to further explore the clinical relevance of the vitamin D pathway and the potential role for vitamin D supplementation in T-LGLL.

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Decreased expression of vitamin D receptor may contribute to the hyperimmune status of patients with acquired aplastic anemia

Cited by 8 publications

References 44 publications

Vitamin D in hematological disorders and malignancies

Vitamin D in hematological disorders and malignancies

Vitamin D deficiency in early implant failure: two case reports

Calcitriol-mediated reduction in IFN-γ output in T cell large granular lymphocytic leukemia requires vitamin D receptor upregulation

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