PMID- 23080369
OWN - NLM
STAT- MEDLINE
DCOM- 20130423
LR  - 20211203
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 57
IP  - 3
DP  - 2013 Mar
TI  - Inhibition of mammalian target of rapamycin aggravates the respiratory burst 
      defect of neutrophils from decompensated patients with cirrhosis.
PG  - 1163-71
LID - 10.1002/hep.26109 [doi]
AB  - Cirrhosis is commonly accompanied by impaired defense functions of 
      polymorphonuclear leucocytes (PMNs), increased patient susceptibility to 
      infections, and hepatocellular carcinoma (HCC). PMN antimicrobial activity is 
      dependent on a massive production of reactive oxygen species (ROS) by 
      nicotinamide adenine dinucleotide phosphate (NADPH) 2 (NADPH oxidase 2; NOX2), 
      termed respiratory burst (RB). Rapamycin, an antagonist of mammalian target of 
      rapamycin (mTOR), may be used in the treatment of HCC and in transplanted 
      patients. However, the effect of mTOR inhibition on the PMN RB of patients with 
      cirrhosis remains unexplored and was studied here using the bacterial peptide, 
      formyl-Met-Leu-Phe (fMLP), as an RB inducer. fMLP-induced RB of PMN from patients 
      with decompensated alcoholic cirrhosis was strongly impaired (30%-35% of control) 
      as a result of intracellular signaling alterations. Blocking mTOR activation 
      (phospho-S2448-mTOR) with rapamycin further aggravated the RB defect. Rapamycin 
      also inhibited the RB of healthy PMNs, which was associated with impaired 
      phosphorylation of the NOX2 component, p47phox (phox: phagocyte oxidase), on its 
      mitogen-activated protein kinase (MAPK) site (S345) as well as a preferential 
      inhibition of p38-MAPK relative to p44/42-MAPK. However, rapamycin did not alter 
      the fMLP-induced membrane association of p47phox and p38-MAPK in patients' PMNs, 
      but did prevent their phosphorylation at the membranes. The mTOR contribution to 
      fMLP-induced RB, phosphorylation of p47phox and p38-MAPK was further confirmed by 
      mTOR knockdown in HL-60 cells. Finally, rapamycin impaired PMN bactericidal 
      activity, but not bacterial uptake. CONCLUSION: mTOR significantly up-regulates 
      the PMN RB of patients with cirrhosis by p38-MAPK activation. Consequently, mTOR 
      inhibition by rapamycin dramatically aggravates their PMN RB defect, which may 
      increase patients' susceptibility to infection. Thus, concerns should be raised 
      about the use of rapamycin in immuno-depressed patients.
CI  - Copyright (c) 2012 American Association for the Study of Liver Diseases.
FAU - Rolas, Loic
AU  - Rolas L
AD  - INSERM U773, CRB3, Faculte de Medecine X. Bichat, Paris, France.
FAU - Makhezer, Nesrine
AU  - Makhezer N
FAU - Hadjoudj, Soumeya
AU  - Hadjoudj S
FAU - El-Benna, Jamel
AU  - El-Benna J
FAU - Djerdjouri, Bahia
AU  - Djerdjouri B
FAU - Elkrief, Laure
AU  - Elkrief L
FAU - Moreau, Richard
AU  - Moreau R
FAU - Perianin, Axel
AU  - Perianin A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130204
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 59880-97-6 (N-Formylmethionine Leucyl-Phenylalanine)
RN  - 65929-03-5 (formylmethionyl-leucyl-phenylalanine methyl ester)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.1 (neutrophil cytosolic factor 1)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Cytosol/metabolism
MH  - Drug Interactions
MH  - Escherichia coli Infections/immunology/metabolism
MH  - Female
MH  - HL-60 Cells
MH  - Humans
MH  - Liver Cirrhosis, Alcoholic/drug therapy/immunology/*metabolism
MH  - MAP Kinase Signaling System/drug effects/immunology
MH  - Male
MH  - Middle Aged
MH  - N-Formylmethionine Leucyl-Phenylalanine/analogs & derivatives/pharmacology
MH  - NADPH Oxidases/metabolism
MH  - Neutrophils/immunology/*metabolism/microbiology
MH  - Phagocytosis/immunology
MH  - Phosphorylation/drug effects/immunology
MH  - Respiratory Burst/drug effects/*immunology
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/immunology/*metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
EDAT- 2012/10/20 06:00
MHDA- 2013/04/24 06:00
CRDT- 2012/10/20 06:00
PHST- 2012/04/28 00:00 [received]
PHST- 2012/10/03 00:00 [accepted]
PHST- 2012/10/20 06:00 [entrez]
PHST- 2012/10/20 06:00 [pubmed]
PHST- 2013/04/24 06:00 [medline]
AID - 10.1002/hep.26109 [doi]
PST - ppublish
SO  - Hepatology. 2013 Mar;57(3):1163-71. doi: 10.1002/hep.26109. Epub 2013 Feb 4.