Submitted on March 17, 2008
Revised on April 29, 2008
Accepted on May 3, 2008
Upregulation of GRAIL is Associated with Remission of Ulcerative Colitis
Satoshi Egawa1, Hideki Iijima1*, Shinichiro Shinzaki1, Sachiko Nakajima1, Jun Wang1, Jumpei Kondo1, Shuji Ishii1, Toshiyuki Yoshio1, Takanobu Irie1, Tsutomu Nishida1, Yoshimi Kakiuchi1, Masakazu Yasumaru1, Harumasa Yoshihara2, Tatsuya Kanto1, Masahiko Tsujii1, Shingo Tsuji1, and Norio Hayashi1
1 Osaka University Graduate School of Medicine
2 Osaka Rosai Hospital
* To whom correspondence should be addressed. E-mail: hiijima{at}gh.med.osaka-u.ac.jp.
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 non-anergic 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 active UC, UC in remission, and HV. These data suggest that GRAIL plays an important role in maintaining remission in patients with UC.
