PMID- 30267995
OWN - NLM
STAT- MEDLINE
DCOM- 20191003
LR  - 20191007
IS  - 1872-8421 (Electronic)
IS  - 0165-5728 (Linking)
VI  - 324
DP  - 2018 Nov 15
TI  - 1,25-Dihydroxyvitamin D(3) increases the methionine cycle, CD4(+) T cell DNA 
      methylation and Helios(+)Foxp3(+) T regulatory cells to reverse autoimmune 
      neurodegenerative disease.
PG  - 100-114
LID - S0165-5728(18)30224-8 [pii]
LID - 10.1016/j.jneuroim.2018.09.008 [doi]
AB  - We investigated how one calcitriol dose plus vitamin D(3) reverses experimental 
      autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This protocol 
      rapidly increased CD4(+) T cell Ikzf2 transcripts, Helios protein, and 
      CD4(+)Helios(+)FoxP3(+) T regulatory cells. It also rapidly increased CD4(+) T 
      cell Bhmt1 transcripts, betaine:homocysteine methyltransferase-1 (BHMT1) enzyme 
      activity, and global DNA methylation. BHMT1 transmethylates homocysteine to 
      replenish methionine. Targeting the Vdr gene in T cells decreased Ikzf2 and Bhmt1 
      gene expression, reduced DNA methylation, and elevated systemic homocysteine in 
      mice with EAE. We hypothesize that calcitriol drives a transition from 
      encephalitogenic CD4(+) T cell to Treg cell dominance by upregulating Ikzf2 and 
      Bhmt1, recycling homocysteine to methionine, reducing homocysteine toxicity, 
      maintaining DNA methylation, and stabilizing CD4(+)Helios(+)FoxP3(+)Tregulatory 
      cells. Conserved vitamin D-responsive element (VDRE)-type sequences in the Bhmt1 
      and Ikzf2 promoters, the universal need for methionine in epigenetic regulation, 
      and betaine's protective effects in MTHFR-deficiency suggest similar regulatory 
      mechanisms exist in humans.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Moore, Jerott R
AU  - Moore JR
AD  - Department of Biochemistry, College of Agricultural and Life Sciences, University 
      of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States.
FAU - Hubler, Shane L
AU  - Hubler SL
AD  - Rhapsody Data, LLC, Madison, WI 53705, United States.
FAU - Nelson, Corwin D
AU  - Nelson CD
AD  - Department of Animal Sciences, University of Florida, Gainesville, FL 32611, 
      United States.
FAU - Nashold, Faye E
AU  - Nashold FE
AD  - Department of Biochemistry, College of Agricultural and Life Sciences, University 
      of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States.
FAU - Spanier, Justin A
AU  - Spanier JA
AD  - Rheumatic and Autoimmune Diseases, Center for Immunology, Department of Medicine, 
      University of Minnesota, Minneapolis, MN 55455, United States. Electronic 
      address: span0005@umn.edu.
FAU - Hayes, Colleen E
AU  - Hayes CE
AD  - Department of Biochemistry, College of Agricultural and Life Sciences, University 
      of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, United States. 
      Electronic address: hayes@biochem.wisc.edu.
LA  - eng
GR  - P30 CA014520/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20180921
PL  - Netherlands
TA  - J Neuroimmunol
JT  - Journal of neuroimmunology
JID - 8109498
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - 0 (Zfpn1a2 protein, mouse)
RN  - 1406-16-2 (Vitamin D)
RN  - 66772-14-3 (1,25-dihydroxyvitamin D)
RN  - AE28F7PNPL (Methionine)
RN  - FXC9231JVH (Calcitriol)
SB  - IM
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/*drug effects/immunology/metabolism
MH  - Calcitriol/pharmacology/therapeutic use
MH  - Cells, Cultured
MH  - DNA Methylation/*drug effects/physiology
MH  - DNA-Binding Proteins/immunology/metabolism
MH  - Encephalomyelitis, Autoimmune, Experimental/*drug therapy/immunology/metabolism
MH  - Female
MH  - Forkhead Transcription Factors/immunology/metabolism
MH  - Male
MH  - Methionine/*agonists/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Neurodegenerative Diseases/drug therapy/immunology/metabolism
MH  - T-Lymphocytes, Regulatory/*drug effects/immunology/metabolism
MH  - Transcription Factors/immunology/metabolism
MH  - Vitamin D/*analogs & derivatives/pharmacology/therapeutic use
EDAT- 2018/09/30 06:00
MHDA- 2019/10/08 06:00
CRDT- 2018/09/30 06:00
PHST- 2018/04/28 00:00 [received]
PHST- 2018/09/12 00:00 [revised]
PHST- 2018/09/18 00:00 [accepted]
PHST- 2018/09/30 06:00 [pubmed]
PHST- 2019/10/08 06:00 [medline]
PHST- 2018/09/30 06:00 [entrez]
AID - S0165-5728(18)30224-8 [pii]
AID - 10.1016/j.jneuroim.2018.09.008 [doi]
PST - ppublish
SO  - J Neuroimmunol. 2018 Nov 15;324:100-114. doi: 10.1016/j.jneuroim.2018.09.008. 
      Epub 2018 Sep 21.