title: Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia.
abstract: Large granular lymphocyte leukemia (LGLL) is a rare incurable chronic disease typically characterized by clonal expansion of CD3+ cytotoxic T-cells. Two signal transducer and activator of transcription factors, STAT1 and STAT3, are constitutively active in T-LGLL. Disruption of this activation induces apoptosis in T-LGLL cells. Therefore, considerable efforts are focused on developing treatments that inhibit STAT activation. Calcitriol, the active form of vitamin D, has been shown to decrease STAT1 and STAT3 phosphorylation in cancer cell lines and autoimmune disease mouse models. Thus, we investigated whether calcitriol could be a valid therapeutic for T-LGLL. Calcitriol treatment of the TL-1 cell line (model of T-LGLL) led to decreased phospho-Y701 STAT1 and phospho-Y705 STAT3 and increased vitamin D receptor (VDR) levels. Doses of 10 and 100 nM calcitriol also significantly decreased the inflammatory cytokine IFN-γ in the TL-1 cell line. The overall cell viability did not change when the TL-1 cell line was treated with 0.1 to 1000 nM calcitriol. Studies with primary T-LGLL patient peripheral blood mononuclear cells showed that the majority of T-LGLL patients have detectable VDR and activated STATs in contrast to normal donor controls. Treatment of primary T-LGLL patient cells with calcitriol recapitulated findings from the TL-1 cell line. Overall, our results suggest that calcitriol may reprogram T-cells to decrease essential STAT activation and pro-inflammatory cytokine output. These data support further investigation into calcitriol as an experimental therapeutic for T-LGLL.
authors.affiliation: a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.|b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.
authors.forename: Kristine C
authors.initials: KC
authors.lastname: Olson
authors.affiliation: a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.|b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.|c Department of Pathology , University of Virginia , Charlottesville , VA , USA.
authors.forename: Paige M
authors.initials: PM
authors.lastname: Kulling
authors.affiliation: a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.|b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Olson
authors.affiliation: a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.|b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.
authors.forename: Su-Fern
authors.initials: SF
authors.lastname: Tan
authors.affiliation: a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.|b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Rainbow
authors.affiliation: a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.|b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
authors.affiliation: a University of Virginia Cancer Center , University of Virginia , Charlottesville , VA , USA.|b Department of Medicine, Division of Hematology/Oncology , University of Virginia , Charlottesville , VA , USA.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Loughran
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology; D002117:Calcitriol / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D054066:Leukemia, Large Granular Lymphocytic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism / Q000473:pathology; D014807:Vitamin D / Q000008:administration & dosage
chemical_list: D017252:CD3 Complex; C573415:IFNG protein, human; D018167:Receptors, Calcitriol; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C579457:VDR protein, human; D014807:Vitamin D; D007371:Interferon-gamma; D002117:Calcitriol
keywords: Calcitriol; LGL leukemia; STAT1; STAT3; inflammatory cytokine; peripheral blood mononuclear cells; phosphorylation; vitamin D; vitamin D receptor