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.
Department of Ophthalmology, Hangil Eye Hospital, Incheon, Korea.
Joonhong
J
Sohn
Ju Byung
JB
Chae
Sun Young
SY
Lee
Soo-Youl
SY
Kim
June-Gone
JG
Kim
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