The vitamin D receptor turns off chronically activated T cells

Kulling²,

Cancer Biology & Therapy

et al. 2016

Large granular lymphocyte leukemia (LGLL) is a rare incurable chronic disease typically characterized by clonal expansion of CD3C 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-g 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.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia

Kulling²,

Cancer Biology & Therapy

et al. 2016

“…During the 1980s vitamin D receptors were identified on cells of the immune system (53,54) sparking interest in immunemodulating effects of vitamin D. For IBD, there is a compelling body of evidence from animal models that vitamin D has the capacity to alter immune responses (11,(55)(56)(57) . Vitamin D deficiency, for example, accelerates the development of experimental colitis in IL-10 knock-out mice, (12) whereas treatment with dietary vitamin D and calcium appear to protect against the development of inflammation (58) .…”

Section: Vitamin D Status and Associations With Disease Severity In Cmentioning

confidence: 99%

Vitamin D as a novel therapy in inflammatory bowel disease: new hope or false dawn?

O’Sullivan

2014

Proc. Nutr. Soc.

There is increasing scientific interest in the field of vitamin D research, moving the focus beyond bone health to other disease processes. Low circulating vitamin D levels have been reported as a risk factor for several pathophysiologically divergent diseases, including cancers, diabetes, CVD, multiple sclerosis and inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease (IBD). But, therein, remains the challenge: can any single nutrient contribute to multiple complex disease mechanisms and, ultimately, have therapeutic potential? The aim of this review is to critically evaluate several strands of scientific evidence surrounding vitamin D and inflammation, primarily focusing on IBD. Epidemiological studies suggest an increased incidence of IBD and rheumatoid arthritis in countries of more northern latitudes, mirroring sunlight patterns. A considerable body of evidence supports the anti-inflammatory effects of vitamin D, at least in animal models of IBD. Although it is accepted that suboptimal vitamin D status is common in IBD, some studies suggest that this associates with more severe disease. With regard to treatment, the data are only beginning to emerge from randomised controlled trials to suggest that people with IBD may remain in remission longer when treated with oral vitamin D. In conclusion, several strands of evidence suggest that vitamin D may modify the immune response in IBD. There is a continued need for large well-designed clinical trials and mechanistic studies to determine if, and how, this emerging promise translates into tangible clinical benefits for people with chronic debilitating diseases such as IBD.

“…The inhibitory effects of 1,25(OH) 2 D on T cell production of IL-17, IFN-␥, and IL-2 are identical in human and mouse cells (11,12,24,25). The induction of FoxP3 ϩ T reg cells by 1,25(OH) 2 D has also been demonstrated to occur in human and mouse T cells (11,12,24,25). Some pathways are not identical; for example, the 1,25(OH) 2 D-induced production of cathelicidin occurs only in human but not mouse macrophages (2).…”

Section: Vitamin D and Human Pulmonary Infectionmentioning

confidence: 99%

Vitamin D and Lung Infection

Cantorna

2016

Infect Immun

Self Cite

Available data suggest that vitamin D plays a role in controlling inflammation in the lungs. However, to date vitamin D-induced production of cathelicidin has not been shown to have an effect on the burden of either viruses or bacteria. Future work should continue to determine the effects of vitamin D-regulated mechanisms in the lung and the possible role of cathelicidin against different pulmonary pathogens in vivo.