Inhibition of tissue transglutaminase attenuates lipopolysaccharide-induced inflammation in glial cells through AKT/mTOR signal pathway.
OBJECTIVE
In view of the facts that tTG protein expression level and its enzyme activity increase in AD brains of both individuals and transgenic animals and compelling evidence of the involvement of inflammation in AD pathogenesis, tTG could be involved in the inflammation responses in the brain. In the present study, we examined the effects of the irreversible and the competitive inhibitor of tTG on the condition of lipopolysaccharide-induced mimic inflammation models in glial cells.


METHODS
Western blot and tTG enzyme activity assay were applied to detect tTG and isopeptide protein levels and tTG enzyme activity. The production of nitric oxide and the expression levels of inducible nitric oxide synthase and cyclooxygenase-2 were determined by Griess Reagents and Western blot respectively to assess anti-inflammatory effects. Moreover, the activation of AKT/mTOR signaling pathway was determined to evaluate the underlying mechanism of anti-inflammatory response.


RESULTS
Irreversible and competitive inhibitor of tTG could ameliorate LPS-induced neuroinflammation in glial cells without cytotoxicity. Moreover, AKT/mTOR pathway may be involved in the anti-inflammatory response of tTG inhibitors. Therefore, NTU283 and Cystamine may alleviate inflammatory response in glial cells, probably through, at least partially, inhibiting the activation of AKT/mTOR signaling pathway.


CONCLUSIONS
Our study provided some clues that tTG inhibitors NTU283 and Cystamine might be potential candidates for the treatments of neuroinflammation-related diseases, although more studies needed for further exploration.
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Yirong
Y
Ding
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Ji
J
Zhang
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. Electronic address: ruiwang@ecust.edu.cn.
Rui
R
Wang
D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003538:Cystamine / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
C000613701:1,3-dimethyl-2-((2-oxopropyl)sulfanyl)-1H-imidazol-3-ium; D007093:Imidazoles; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D011503:Transglutaminases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D003538:Cystamine
AKT/mTOR; Glial cells; Neuroinflammation; tTG