A novel therapeutic target in inflammatory uveitis: transglutaminase 2 inhibitor.
OBJECTIVE
Our goal was to investigate the effects of inhibition of transglutaminase 2 (TGase 2) on endotoxin-induced uveitis (EIU) METHODS: EIU was induced in female Lewis rats by single footpad injections of 200 microg of lipopolysaccharide (LPS). TGase 2 inhibitors were administered intraperitoneally 30 minutes before and at the time of LPS administration. Rats were sacrificed 24 hours after injection, and the effects of the TGase 2 inhibitors were evaluated by the number of intraocular inflammatory cells present on histologic sections and by measuring the TGase 2 activity and TGase products in the aqueous humor (AqH). TGase 2 substrates were also assayed in AqH from uveitis patients.


RESULTS
Clinical indications of EIU, the number of cells present on histologic sections, and TGase 2 activity in AqH increased in a time-dependent manner, peaking 24 hours after LPS injection. Inflammation in EIU was significantly reversed by treatment with TGase inhibitors. A 23-kDa cross-linked TGase substrate was identified in the AqH from EIU rats and uveitis patients. MALDI-TOF analysis showed that this substrate in uveitis patients was human Ig kappa chain C region.


CONCLUSIONS
TGase 2 activity and its catalytic product were increased in the AqH of EIU rats. TGase 2 inhibition attenuated the degree of inflammation in EIU. Safe and stable TGase inhibitors may have great potential for the treatment of inflammatory uveitis.
Sohn
Joonhong
J
Department of Ophthalmology, Hangil Eye Hospital, Incheon, Korea.
Chae
Ju Byung
JB
Lee
Sun Young
SY
Kim
Soo-Youl
SY
Kim
June-Gone
JG
D000818:Animals; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008070:Lipopolysaccharides; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D011917:Rats, Inbred Lew; D011503:Transglutaminases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014605:Uveitis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C000717609:Tgm2 protein, rat; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins