PMID- 27512981
OWN - NLM
STAT- MEDLINE
DCOM- 20170202
LR  - 20190212
IS  - 1421-9778 (Electronic)
IS  - 1015-8987 (Linking)
VI  - 39
IP  - 3
DP  - 2016
TI  - Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) 
      Development.
PG  - 985-95
LID - 10.1159/000447806 [doi]
AB  - BACKGROUND/AIMS: Regulatory T cell (Treg) is required for the maintenance of 
      tolerance to various tissue antigens and to protect the host from autoimmune 
      disorders. However, Treg may, indirectly, support cancer progression and 
      bacterial infections. Therefore, a balance of Treg function is pivotal for 
      adequate immune responses. Acid sphingomyelinase (ASM) is a rate limiting enzyme 
      involved in the production of ceramide by breaking down sphingomyelin. Previous 
      studies in T-cells have suggested that ASM is involved in CD28 signalling, T 
      lymphocyte granule secretion, degranulation, and vesicle shedding similar to the 
      formation of phosphatidylserine-exposing microparticles from glial cells. 
      However, whether ASM affects the development of Treg has not yet been described. 
      METHODS: Splenocytes, isolated Naive T lymphocytes and cultured T cells were 
      characterized for various immune T cell markers by flow cytometery. Cell 
      proliferation was measured by Carboxyfluorescein succinimidyl ester (CFSE) dye, 
      cell cycle analysis by Propidium Iodide (PI), mRNA transcripts by q-RT PCR and 
      protein expression by Western Blotting respectively. RESULTS: ASM deficient mice 
      have higher number of Treg compared with littermate control mice. In vitro 
      induction of ASM deficient T cells in the presence of TGF-beta and IL-2 lead to a 
      significantly higher number of Foxp3+ induced Treg (iTreg) compared with control 
      T-cells. Further, ASM deficient iTreg has less AKT (serine 473) phosphorylation 
      and Rictor levels compared with control iTreg. Ceramide C6 led to significant 
      reduction of iTreg in both ASM deficient and WT mice. The reduction in iTreg 
      leads to induction of IL-1beta, IL-6 and IL-17 but not IFN-gamma mRNA levels. 
      CONCLUSION: ASM is a negative regulator of natural and iTreg.
CI  - (c) 2016 The Author(s) Published by S. Karger AG, Basel.
FAU - Zhou, Yuetao
AU  - Zhou Y
AD  - Department of Cardiology, Vascular Medicine and Physiology I, Tuebingen 
      University, Tuebingen, Germany.
FAU - Salker, Madhuri S
AU  - Salker MS
FAU - Walker, Britta
AU  - Walker B
FAU - Munzer, Patrick
AU  - Munzer P
FAU - Borst, Oliver
AU  - Borst O
FAU - Gawaz, Meinrad
AU  - Gawaz M
FAU - Gulbins, Erich
AU  - Gulbins E
FAU - Singh, Yogesh
AU  - Singh Y
FAU - Lang, Florian
AU  - Lang F
LA  - eng
PT  - Journal Article
DEP - 20160812
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (5-(6)-carboxyfluorescein diacetate succinimidyl ester)
RN  - 0 (Carrier Proteins)
RN  - 0 (Ceramides)
RN  - 0 (Fluoresceins)
RN  - 0 (Fluorescent Dyes)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxp3 protein, mouse)
RN  - 0 (Interleukin-2)
RN  - 0 (Interleukins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Succinimides)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (rictor protein, mouse)
RN  - 36015-30-2 (Propidium)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.4.- (acid sphingomyelinase-1)
RN  - EC 3.1.4.12 (Sphingomyelin Phosphodiesterase)
RN  - F1X8L2B00J (N-(alpha-hydroxyoctadecanoyl)phytosphingosine)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/genetics/immunology
MH  - Cell Differentiation/drug effects/*immunology
MH  - Cell Proliferation
MH  - Cell Separation
MH  - Ceramides/immunology/metabolism
MH  - Female
MH  - Fluoresceins
MH  - Fluorescent Dyes
MH  - Forkhead Transcription Factors/genetics/immunology
MH  - Gene Expression
MH  - Gene Expression Regulation
MH  - Immunity, Innate
MH  - Interleukin-2/pharmacology
MH  - Interleukins/genetics/immunology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Phosphorylation
MH  - Primary Cell Culture
MH  - Propidium
MH  - Proto-Oncogene Proteins c-akt/genetics/immunology
MH  - RNA, Messenger/*genetics/immunology
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Signal Transduction
MH  - Sphingomyelin Phosphodiesterase/deficiency/*genetics/immunology
MH  - Spleen/drug effects/*immunology/pathology
MH  - Succinimides
MH  - T-Lymphocytes, Regulatory/drug effects/*immunology/pathology
MH  - Transforming Growth Factor beta/pharmacology
EDAT- 2016/08/12 06:00
MHDA- 2017/02/06 06:00
CRDT- 2016/08/12 06:00
PHST- 2016/07/15 00:00 [accepted]
PHST- 2016/08/12 06:00 [entrez]
PHST- 2016/08/12 06:00 [pubmed]
PHST- 2017/02/06 06:00 [medline]
AID - 000447806 [pii]
AID - 10.1159/000447806 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2016;39(3):985-95. doi: 10.1159/000447806. Epub 2016 Aug 
      12.