PMID- 32612145
OWN - NLM
STAT- MEDLINE
DCOM- 20201210
LR  - 20211204
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 10
IP  - 1
DP  - 2020 Jul 1
TI  - mTOR sustains inflammatory response in celiac disease.
PG  - 10798
LID - 10.1038/s41598-020-67889-4 [doi]
LID - 10798
AB  - Celiac disease (CD) is an enteropathy triggered by the ingestion of gluten 
      proteins in genetically predisposed individuals and characterized by excessive 
      activation of effector immune cells and enhanced production of inflammatory 
      cytokines. However, factors/mechanisms that amplify the ongoing mucosal 
      inflammation in CD are not fully understood. In this study, we assessed whether 
      mammalian target of Rapamycin (mTOR), a pathway that combines intra- and 
      extra-cellular signals and acts as a central regulator for the metabolism, 
      growth, and function of immune and non-immune cells, sustains CD-associated 
      immune response. Our findings indicate that expression of phosphorylated 
      (p)/active form of mTOR is increased in protein lysates of duodenal biopsy 
      samples taken from patients with active CD (ACD) as compared to normal controls. 
      In ACD, activation of mTOR occurs mainly in the epithelial compartment and 
      associates with enhanced expression of p-4EBP, a downstream target of mTOR 
      complex (mTORC)1, while expression of p-Rictor, a component of mTORC2, is not 
      increased. Stimulation of mucosal explants of inactive CD patients with 
      pepsin-trypsin-digested (PT)-gliadin or IFN-gamma/IL-21, two cytokines produced in CD 
      by gluten-specific T cells, increases p-4EBP expression. Consistently, blockade 
      of such cytokines in cultures of ACD mucosal explants reduces p-4EBP. Finally, we 
      show that inhibition of mTORC1 with rapamycin in ACD mucosal explants reduces 
      p-4EBP and production of IL-15, a master cytokine produced by epithelial cells in 
      this disorder. Our data suggest that ACD inflammation is marked by activation of 
      mTORC1 in the epithelial compartment.
FAU - Sedda, S
AU  - Sedda S
AD  - Department of Systems Medicine, University of "Tor Vergata", Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Dinallo, V
AU  - Dinallo V
AD  - Department of Systems Medicine, University of "Tor Vergata", Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Marafini, I
AU  - Marafini I
AD  - Department of Systems Medicine, University of "Tor Vergata", Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Franze, E
AU  - Franze E
AD  - Department of Systems Medicine, University of "Tor Vergata", Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Paoluzi, O A
AU  - Paoluzi OA
AD  - Department of Systems Medicine, University of "Tor Vergata", Via Montpellier, 1, 
      00133, Rome, Italy.
FAU - Izzo, R
AU  - Izzo R
AD  - Medpace Spain, Madrid, Spain.
FAU - Giuffrida, P
AU  - Giuffrida P
AD  - Dipartimento Di Medicina Interna, Fondazione IRCCS Policlinico San Matteo, 
      Universita Di Pavia, Pavia, Italy.
FAU - Di Sabatino, A
AU  - Di Sabatino A
AUID- ORCID: 0000-0002-0302-8645
AD  - Dipartimento Di Medicina Interna, Fondazione IRCCS Policlinico San Matteo, 
      Universita Di Pavia, Pavia, Italy.
FAU - Corazza, G R
AU  - Corazza GR
AD  - Dipartimento Di Medicina Interna, Fondazione IRCCS Policlinico San Matteo, 
      Universita Di Pavia, Pavia, Italy.
FAU - Monteleone, G
AU  - Monteleone G
AD  - Department of Systems Medicine, University of "Tor Vergata", Via Montpellier, 1, 
      00133, Rome, Italy. Gi.Monteleone@med.uniroma2.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200701
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (IFNG protein, human)
RN  - 0 (Interleukins)
RN  - 82115-62-6 (Interferon-gamma)
RN  - 9007-90-3 (Gliadin)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - MKM3CA6LT1 (interleukin-21)
SB  - IM
MH  - Biopsy
MH  - Celiac Disease/*immunology/pathology
MH  - Duodenum/*immunology/pathology
MH  - Female
MH  - Gliadin/immunology
MH  - Humans
MH  - Inflammation/immunology/pathology
MH  - Interferon-gamma/immunology
MH  - Interleukins/immunology
MH  - Intestinal Mucosa/*immunology/pathology
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1/immunology
MH  - Mechanistic Target of Rapamycin Complex 2/immunology
MH  - Phosphorylation/immunology
MH  - T-Lymphocytes/immunology
MH  - TOR Serine-Threonine Kinases/*immunology
PMC - PMC7329835
COIS- Monteleone G has served as an advisory board member for ABBVIE. The remaining 
      authors declare that the research was conducted in the absence of any commercial 
      or financial relationships that could be construed as a potential competing 
      interests.
EDAT- 2020/07/03 06:00
MHDA- 2020/12/15 06:00
PMCR- 2020/07/01
CRDT- 2020/07/03 06:00
PHST- 2019/08/01 00:00 [received]
PHST- 2020/06/02 00:00 [accepted]
PHST- 2020/07/03 06:00 [entrez]
PHST- 2020/07/03 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/07/01 00:00 [pmc-release]
AID - 10.1038/s41598-020-67889-4 [pii]
AID - 67889 [pii]
AID - 10.1038/s41598-020-67889-4 [doi]
PST - epublish
SO  - Sci Rep. 2020 Jul 1;10(1):10798. doi: 10.1038/s41598-020-67889-4.