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

Publication date: Available online 20 July 2017 Source:The Journal of Steroid Biochemistry and Molecular Biology Author(s): M. Paige Kulling, C. Kristine Olson, L. Thomas Olson, E. Cait Hamele, N. Kathryn Carter, J. David Feith, P. Thomas Loughran 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 corr...
Source: The Journal of Steroid Biochemistry and Molecular Biology - Category: Biochemistry Source Type: research