1,25-Dihydroxyvitamin D3 Transcriptional Repression of Interleukin-17A Expression and Th17-Related Autoimmunity

In a new Molecular and Cellular Biology study, Sneha Joshi and colleagues from the University of Medicine and Dentistry of New Jersey, Newark demonstrate that the reversal of paralysis in EAE mice by 1,25-Dihydroxyvitamin D3 correlates with reduced IL-17A-secreting CD4+ T cells, and that the mechanism involved in 1,25-Dihydroxyvitamin D3-mediated suppression of IL-17A induction involves transcriptional repression.

1,25-Dihydroxyvitamin D3 controls bone and calcium metabolism but is also involved in immunoregulation via the nuclear Vitamin D receptor (VDR) expressed in antigen-presenting cells and activated T cells.

The hormone inhibits dendritic cells differentiation and maturation, and preferentially targets T helper 1 (Th1) cell activity by inhibiting the secretion of interleukin (IL)-2 and IL-12. Epidemiologic studies report an association between vitamin D insufficiency and multiple sclerosis expression, whereas in animal models of autoimmunity, 1,25-Dihydroxyvitamin D3 prevents the development of experimental autoimmune encephalomyelitis (EAE), reduces the incidence of diabetes, and attenuates murine lupus.

Recent evidence indicates that 1,25-Dihydroxyvitamin D3 reduces the expression of IL-17 in T cells from patients with multiple sclerosis and rheumatoid arthritis. Thus, it is possible that vitamin D exerts some of its effects on inflammation and autoimmune disease through the regulation of Th17 cells.

In the Molecular and Cellular Biology study the authors report that the active form of vitamin D down-regulates IL-17A expression by dissociation of histone acetylase activity from the IL-17A promoter and recruitment of histone deacetylase (HDAC) and VDR/retinoid X receptor (RXR) binding to the nuclear factor for activated T cells (NFAT) sites.

In addition, the suppressive effect of 1,25-Dihydroxyvitamin D3 involves sequestration of runt-related transcription factor 1 (Runx1) by 1,25-Dihydroxyvitamin D3 /VDR, as well as induction by 1,25-Dihydroxyvitamin D3 of forkhead box P3 (Foxp3), which is known to interact with Runx1 and NFAT, and thus can negatively regulate IL-17A transcription.

Therefore, the interaction among NFAT, VDR, Foxp3, and Runx1 is involved, at least in part, in suppression of proinflammatory Th17 responses by 1,25-Dihydroxyvitamin D3.

This and other studies suggest that 1,25-Dihydroxyvitamin D3 or its analogs may represent therapeutic targets for the control of Th17-related autoimmune diseases.

SOURCE:  Mol Cell Biol 2011, 17:3653. Epub 2011 Jul 11.

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