A Novel Therapeutic Target in Inflammatory Uveitis: Transglutaminase 2 Inhibitor |
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Authors: | Joonhong Sohn Ju Byung Chae Sun Young Lee Soo-Youl Kim and June-Gone Kim |
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Institution: | 1Department of Ophthalmology, Hangil Eye Hospital, Incheon, Korea.;2Department of Ophthalmology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.;3Molecular Oncology Branch, Division of Basic & Applied Sciences, National Cancer Center, Seoul, Korea. |
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Abstract: | PurposeOur goal was to investigate the effects of inhibition of transglutaminase 2 (TGase 2) on endotoxin-induced uveitis (EIU)MethodsEIU was induced in female Lewis rats by single footpad injections of 200 µg 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.ResultsClinical 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.ConclusionsTGase 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. |
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Keywords: | Endotoxin-induced uveitis Lipopolysaccharides Transglutaminases |
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