PMID- 30306723
OWN - NLM
STAT- MEDLINE
DCOM- 20190607
LR  - 20210109
IS  - 2050-4527 (Electronic)
IS  - 2050-4527 (Linking)
VI  - 6
IP  - 4
DP  - 2018 Dec
TI  - ATP promotes immunosuppressive capacities of mesenchymal stromal cells by 
      enhancing the expression of indoleamine dioxygenase.
PG  - 448-455
LID - 10.1002/iid3.236 [doi]
AB  - INTRODUCTION: MSCs are often found within tumors, promote cancer progression and 
      enhance metastasis. MSCs can act as immuosuppressive cells, partially due to the 
      expression of the enzyme indoleamine dioxygenase (IDO) which converts tryptophan 
      to kynurenine. Decreased concentration of tryptophan and increased kynurenine, 
      both interfere with effective immune response. Damage associated molecular 
      patterns (DAMPs) including ATP are found within the tumor microenvironment, 
      attract MSCs, and influence their biology. METHODS: Bone marrow derived MSCs were 
      exposed to ATP for 4 days, in the presence of 100 ng IFNgamma/mL. Intracellular 
      expression of IDO in MSCs was assessed by FACS. Conditioned media from thus 
      stimulated MSCs was analyzed for kynurenine content and its suppressive effect on 
      lymphocyte proliferation. Apyrase or P2 x 7-receptor antagonist (AZ 11645373) 
      were applied in order to inhibit ATP induced effect on MSCs. RESULTS: We 
      demonstrate, that ATP at concentrations between 0.062 and 0.5 mM increases dose 
      dependently the expression of IDO in MSCs with subsequent increased kynurenine 
      concentrations within the supernatant at about 60%. This effect could be 
      abolished completely in the presence of ATP degrading enzyme (apyrase) or when 
      MSCs were pretreated with a P2 x 7-receptor antagonist (AZ 11645373). 
      Consistently, supernatants from MSCs stimulated with ATP, inhibited lymphocyte 
      proliferation from 65% to 16%. CONCLUSIONS: We characterized ATP as a DAMP family 
      member responsible for necrosis-induced immunomodulation. Given the increased 
      concentration of DAMPs within tumor tissue and the fact that DAMPs can act as 
      chemotattractants to MSCs, our results have implications for therapeutic 
      strategies targeting the tumor microenvironment.
CI  - (c) 2018 The Authors. Immunity, Inflammation and Disease Published by John Wiley & 
      Sons Ltd.
FAU - Lotfi, Ramin
AU  - Lotfi R
AUID- ORCID: 0000-0002-8125-0591
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
AD  - Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red 
      Cross Blood Services Baden-Wuerttemberg-Hessen, Ulm, Germany.
FAU - Steppe, Lena
AU  - Steppe L
AUID- ORCID: 0000-0003-0968-5627
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
FAU - Hang, Regina
AU  - Hang R
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
FAU - Rojewski, Markus
AU  - Rojewski M
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
FAU - Massold, Marina
AU  - Massold M
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
FAU - Jahrsdorfer, Bernd
AU  - Jahrsdorfer B
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
AD  - Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red 
      Cross Blood Services Baden-Wuerttemberg-Hessen, Ulm, Germany.
FAU - Schrezenmeier, Hubert
AU  - Schrezenmeier H
AD  - Institute for Transfusion Medicine, University of Ulm, Ulm, Germany.
AD  - Institute for Clinical Transfusion Medicine and Immunogenetics Ulm, German Red 
      Cross Blood Services Baden-Wuerttemberg-Hessen, Ulm, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181010
PL  - England
TA  - Immun Inflamm Dis
JT  - Immunity, inflammation and disease
JID - 101635460
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 343-65-7 (Kynurenine)
RN  - 8DUH1N11BX (Tryptophan)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 3.6.1.5 (Apyrase)
SB  - IM
MH  - Adenosine Triphosphate/*pharmacology
MH  - Apyrase/pharmacology
MH  - Cell Proliferation
MH  - Cells, Cultured
MH  - Culture Media, Conditioned/chemistry
MH  - Humans
MH  - *Immune Tolerance
MH  - Immunomodulation
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/*genetics
MH  - Kynurenine/metabolism
MH  - Lymphocyte Activation
MH  - Mesenchymal Stem Cells/*immunology
MH  - Tryptophan/metabolism
PMC - PMC6247240
OTO - NOTNLM
OT  - DAMPs
OT  - cancer
OT  - inflammation
OT  - mesenchymal stromal cells
OT  - wound healing
EDAT- 2018/10/12 06:00
MHDA- 2019/06/08 06:00
PMCR- 2018/10/10
CRDT- 2018/10/12 06:00
PHST- 2018/07/12 00:00 [received]
PHST- 2018/08/04 00:00 [accepted]
PHST- 2018/10/12 06:00 [pubmed]
PHST- 2019/06/08 06:00 [medline]
PHST- 2018/10/12 06:00 [entrez]
PHST- 2018/10/10 00:00 [pmc-release]
AID - IID3236 [pii]
AID - 10.1002/iid3.236 [doi]
PST - ppublish
SO  - Immun Inflamm Dis. 2018 Dec;6(4):448-455. doi: 10.1002/iid3.236. Epub 2018 Oct 
      10.