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Am J Physiol Gastrointest Liver Physiol 295: G163-G169, 2008. First published May 8, 2008; doi:10.1152/ajpgi.90242.2008
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INFLAMMATION/IMMUNITY/MEDIATORS

Upregulation of GRAIL is associated with remission of ulcerative colitis

Satoshi Egawa,1 Hideki Iijima,1 Shinichiro Shinzaki,1 Sachiko Nakajima,1 Jun Wang,1 Jumpei Kondo,1 Shuji Ishii,1 Toshiyuki Yoshio,1 Takanobu Irie,1 Tsutomu Nishida,1 Yoshimi Kakiuchi,1 Masakazu Yasumaru,1 Harumasa Yoshihara,3 Tatsuya Kanto,1,2 Masahiko Tsujii,1 Shingo Tsuji,1 and Norio Hayashi1

Departments of 1Gastroenterology and Hepatology, 2Dendritic Cells and Clinical Applications, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; 3Department of Gastroenterology, Osaka Rosai Hospital, Sakai, Osaka, Japan

Submitted 17 March 2008 ; accepted in final form 3 May 2008

Abrogating tolerance against unidentified antigens is a critical step in the pathogenesis of ulcerative colitis (UC). T cell anergy, one of the main mechanisms of tolerance, has been shown to be induced by E3 ubiquitin ligases, such as gene related to anergy in lymphocytes (GRAIL), Itch, and c-Cbl in mice. However, it is not well known whether these E3 ligases play roles in human diseases. The pathophysiological role of the E3 ligases in patients with UC was investigated. At first, the expression of GRAIL, Itch, and c-Cbl in human anergic T cells was analyzed by quantitative RT-PCR and Western immunoblotting. Next, the mRNA expression of the E3 ligases was analyzed in peripheral CD4+ T cells of 20 patients with UC and 10 healthy volunteers (HV). mRNA expression was analyzed in patients with active UC before and after treatment with prednisolone and leukocytapheresis. Anergic human CD4+ T cells expressed significantly higher levels of GRAIL, Itch, and c-Cbl than nonanergic cells. GRAIL expression was significantly higher in patients with UC in remission than in patients with active disease and in HV (P < 0.01). The level of GRAIL expression was also significantly increased in patients with active disease whose clinical activity index scores improved after treatment (P < 0.05). There were no significant differences in Itch and c-Cbl expression among patients with active UC, patients with UC in remission, and HV. These data suggest that GRAIL plays an important role in maintaining remission in patients with UC.

T cell anergy; E3 ubiquitin ligase; tolerance; inflammatory bowel disease


Address for reprint requests and other correspondence: H. Iijima, Dept. of Gastroenterology and Hepatology, Osaka Univ. Graduate School of Medicine, 2-2 K1 Yamadaoka, Suita, Osaka 565-0871, Japan (e-mail: hiijima{at}gh.med.osaka-u.ac.jp)






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