PMID- 25547897
OWN - NLM
STAT- MEDLINE
DCOM- 20151216
LR  - 20211203
IS  - 1029-2470 (Electronic)
IS  - 1029-2470 (Linking)
VI  - 49
IP  - 3
DP  - 2015 Mar
TI  - Transglutaminase 2 is involved in homocysteine-induced activation of human THP-1 
      monocytes.
PG  - 299-308
LID - 10.3109/10715762.2014.1002495 [doi]
AB  - Aberrant transglutaminase 2 (TG2) expression and protein cross-linking activity 
      have been associated with several chronic neurodegenerative disorders in which 
      inflammatory processes triggered by activated microglia and monocytes play a key 
      role, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral 
      sclerosis, and multiple sclerosis. Interestingly, mild-to-moderate 
      hyperhomocysteinemia (HHcy), corresponding to increased plasma homocysteine (Hcy) 
      concentrations in the range 16-60 muM, have recently been associated with the 
      above-cited diseases. Using THP-1 monocytes, here we investigated the role of TG2 
      in cell response to mildly elevated Hcy concentrations. A five-day incubation 
      with Hcy ( approximately 25 muM) increased reactive oxygen species, peroxide lipids, as well as 
      8-hydroxyguanosine levels by twofold, and decreased the endogenous cell 
      antioxidant defenses, that is reduced glutathione, by 50% in Hcy-exposed cultures 
      compared with controls (p < 0.01). Hcy-induced oxidative stress was associated 
      with increases in TG2 expression and activity, as well as nuclear factor kappa B 
      activation. Notably, the latter was reduced in the presence of the TG-specific 
      inhibitor R283. Hcy exposure also significantly increased the mRNA levels of 
      tumor necrosis factor alpha, interleukin (IL)-6, and IL-1beta, as well as the level 
      of Hcy-inducible endoplasmic reticulum (ER) stress protein, a marker of ER 
      stress, in Hcy-exposed cultures compared with controls. Notably, these effects 
      were dramatically reduced by R283. These preliminary findings indicate that TG2 
      plays a key role in Hcy-induced activation of THP-1 monocytes, involving 
      oxidative as well as ER stress and inflammation. This underlines the potential of 
      TG2 inhibition in the therapeutic management of inflammatory processes 
      contributing to neurodegenerative disorders associated with mild HHcy.
FAU - Curro, M
AU  - Curro M
AD  - Department of Biomedical Sciences and Morphofunctional Imaging, University of 
      Messina , Messina , Italy.
FAU - Gangemi, C
AU  - Gangemi C
FAU - Gugliandolo, A
AU  - Gugliandolo A
FAU - Risitano, R
AU  - Risitano R
FAU - Ferlazzo, N
AU  - Ferlazzo N
FAU - Ientile, R
AU  - Ientile R
FAU - Caccamo, D
AU  - Caccamo D
LA  - eng
PT  - Journal Article
DEP - 20150204
PL  - England
TA  - Free Radic Res
JT  - Free radical research
JID - 9423872
RN  - 0 (Antioxidants)
RN  - 0 (Cytokines)
RN  - 0 (NF-kappa B)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - EC 2.3.2.13 (Protein Glutamine gamma Glutamyltransferase 2)
RN  - EC 2.3.2.13 (Transglutaminases)
RN  - EC 3.6.1.- (GTP-Binding Proteins)
SB  - IM
MH  - Antioxidants/metabolism
MH  - Cell Line
MH  - Cytokines/genetics
MH  - Endoplasmic Reticulum Stress
MH  - GTP-Binding Proteins/genetics/*metabolism
MH  - Homocysteine/*pharmacology
MH  - Humans
MH  - Monocytes/*enzymology/immunology
MH  - NF-kappa B/metabolism
MH  - Oxidative Stress
MH  - Protein Glutamine gamma Glutamyltransferase 2
MH  - Transglutaminases/genetics/*metabolism
MH  - Up-Regulation
OTO - NOTNLM
OT  - ER stress
OT  - homocysteine
OT  - inflammation
OT  - oxidative stress
OT  - transglutaminase 2
EDAT- 2014/12/31 06:00
MHDA- 2015/12/19 06:00
CRDT- 2014/12/31 06:00
PHST- 2014/12/31 06:00 [entrez]
PHST- 2014/12/31 06:00 [pubmed]
PHST- 2015/12/19 06:00 [medline]
AID - 10.3109/10715762.2014.1002495 [doi]
PST - ppublish
SO  - Free Radic Res. 2015 Mar;49(3):299-308. doi: 10.3109/10715762.2014.1002495. Epub 
      2015 Feb 4.