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1,25-Dihydroxyvitamin D3-3-bromoacetate, a novel vitamin D analog induces immunosuppression through PI3K/Akt/mTOR signaling cascade.

Abstract：

PURPOSE:The molecular mechanism responsible for the immunomodulatory effect of 1,25-dihydroxyvitamin D3 (Vit-D) is still not well elucidated. Unavoidable systemic toxicity of Vit-D has encouraged to develop more potent and less toxic Vit-D analogs, such as 1,25-dihydroxyvitamin D3-3-bromoacetate (BE). Our aim was to explore the immunosuppressive effect of BE and its molecular mechanism in autoimmune diseases. METHOD:Magnetically sorted CD3(+) T cells (T cells) from PBMCs of psoriasis and autoimmune arthritis patients were cultured with/without BE and Vit-D followed by proliferation (MTT, CFSE dilution assays) and apoptosis assays (annexin V). Immunoblot was performed to determine the signaling cascade responsible for the antiproliferative effect. RESULTS:In MTT assay, BE (OD: 0.64±0.08) markedly inhibited the anti-CD3/CD28 stimulated proliferation of T cells (OD: 1.8±0.30, p<0.001) and at equivalent doses, the inhibitory effect was more than that of Vit-D (OD: 0.91±0.11, p<0.05). The antiproliferative effect of BE was extended to activated CD4(+) and CD8(+) memory T cells (CD45RA(-)CD11a(+)) without much effect on the naïve T cells. BE induced more apoptosis of T cells (45.01±4.27%, p<0.01) compared to untreated cells (3.45±1.8%), and the proapoptotic effect was markedly more than that of Vit-D (26.1±2.05%, p<0.05). BE effectively inhibited the anti-CD3/CD28-induced phosphorylation of Akt and mTOR and in both, BE showed more potency than Vit-D (p<0.05). CONCLUSION:Topical Vit-D is being used successfully in psoriasis for years. However, its potency is less compared to topical corticosteroids. The de novo BE showed significantly more immunosuppression than conventional Vit-D and the immunosuppressive effect is PI3K/Akt/mTOR dependent. Our results indicate that BE could be an effective therapeutic agent for psoriasis and other T-cell-mediated autoimmune diseases.

journal_name

Int Immunopharmacol

journal_title

International immunopharmacology

authors

Datta-Mitra A,Mitra A,Ray R,Raychaudhuri SP,Kundu-Raychaudhuri S

doi

10.1016/j.intimp.2013.08.009

subject

Has Abstract

pub_date

2013-11-01 00:00:00

pages

744-51

issue

eissn

1567-5769

issn

1878-1705

pii

S1567-5769(13)00330-5

journal_volume

pub_type

杂志文章

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1,25-Dihydroxyvitamin D3-3-bromoacetate, a novel vitamin D analog induces immunosuppression through PI3K/Akt/mTOR signaling cascade.