PMID- 27035541
OWN - NLM
STAT- MEDLINE
DCOM- 20161226
LR  - 20211203
IS  - 1791-244X (Electronic)
IS  - 1107-3756 (Linking)
VI  - 37
IP  - 5
DP  - 2016 May
TI  - Differential effects of the two amino acid sensing systems, the GCN2 kinase and 
      the mTOR complex 1, on primary human alloreactive CD4(+) T-cells.
PG  - 1412-20
LID - 10.3892/ijmm.2016.2547 [doi]
AB  - Amino acid deprivation activates general control nonderepressible 2 (GCN2) kinase 
      and inhibits mammalian target of rapamycin (mTOR), affecting the immune response. 
      In this study, the effects of GCN2 kinase activation or mTOR inhibition on human 
      alloreactive CD4+ T-cells were evaluated. The mixed lymphocyte reaction, as a 
      model of alloreactivity, the GCN2 kinase activator, tryptophanol (TRP), and the 
      mTOR complex 1 inhibitor, rapamycin (RAP), were used. Both TRP and RAP suppressed 
      cell proliferation and induced cell apoptosis. These events were p53-independent 
      in the case of RAP, but were accompanied by an increase in p53 levels in the case 
      of TRP. TRP decreased the levels of the Th2 signature transcription factor, 
      GATA-3, as RAP did, yet the latter also decreased the levels of the Th1 and Th17 
      signature transcription factors, T-bet and RORgammat, whereas it increased the levels 
      of the Treg signature transcription factor, FoxP3. Accordingly, TRP decreased the 
      production of interleukin (IL)-4, as RAP did, but RAP also decreased the levels 
      of interferon-gamma (IFN-gamma) and IL-17. Both TRP and RAP increased the levels of 
      IL-10. As regards hypoxia-inducible factor-1alpha (HIF-1alpha), which upregulates the 
      Th17/Treg ratio, its levels were decreased by RAP. TRP increased the HIF-1alpha 
      levels, which however, remained inactive. In conclusion, our findings indicate 
      that, in primary human alloreactive CD4+ T-cells, the two systems that sense 
      amino acid deprivation affect cell proliferation, apoptosis and differentiation 
      in different ways or through different mechanisms. Both mTOR inhibition and GCN2 
      kinase activation exert immunosuppressive effects, since they inhibit cell 
      proliferation and induce apoptosis. As regards CD4+ T-cell differentiation, mTOR 
      inhibition exerted a more profound effect, since it suppressed differentiation 
      into the Th1, Th2 and Th17 lineages, while it induced Treg differentiation. On 
      the contrary, the activation of GCN2 kinase suppressed only Th2 differentiation.
FAU - Eleftheriadis, Theodoros
AU  - Eleftheriadis T
AD  - Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, 
      Greece.
FAU - Pissas, Georgios
AU  - Pissas G
AD  - Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, 
      Greece.
FAU - Antoniadi, Georgia
AU  - Antoniadi G
AD  - Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, 
      Greece.
FAU - Liakopoulos, Vassilios
AU  - Liakopoulos V
AD  - Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, 
      Greece.
FAU - Tsogka, Konstantina
AU  - Tsogka K
AD  - Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, 
      Greece.
FAU - Sounidaki, Maria
AU  - Sounidaki M
AD  - Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, 
      Greece.
FAU - Stefanidis, Ioannis
AU  - Stefanidis I
AD  - Department of Nephrology, Medical School, University of Thessaly, 41110 Larissa, 
      Greece.
LA  - eng
PT  - Journal Article
DEP - 20160401
PL  - Greece
TA  - Int J Mol Med
JT  - International journal of molecular medicine
JID - 9810955
RN  - 0 (Amino Acids)
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (EIF2AK4 protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Adult
MH  - Amino Acids/*pharmacology
MH  - Biomarkers
MH  - CD4-Positive T-Lymphocytes/cytology/*drug effects/*metabolism
MH  - Cell Differentiation/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cytokines/metabolism
MH  - Female
MH  - Gene Expression Regulation/drug effects
MH  - Humans
MH  - Lymphocyte Activation
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Middle Aged
MH  - Multiprotein Complexes/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Transcription Factors/genetics/metabolism
EDAT- 2016/04/02 06:00
MHDA- 2016/12/27 06:00
CRDT- 2016/04/02 06:00
PHST- 2015/12/16 00:00 [received]
PHST- 2016/03/11 00:00 [accepted]
PHST- 2016/04/02 06:00 [entrez]
PHST- 2016/04/02 06:00 [pubmed]
PHST- 2016/12/27 06:00 [medline]
AID - 10.3892/ijmm.2016.2547 [doi]
PST - ppublish
SO  - Int J Mol Med. 2016 May;37(5):1412-20. doi: 10.3892/ijmm.2016.2547. Epub 2016 Apr 
      1.