Upregulation of GRAIL is associated with remission of ulcerative colitis.
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.
Egawa
Satoshi
S
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1 Yamadaoka, Suita, Osaka 565-0871, Japan.
Iijima
Hideki
H
Shinzaki
Shinichiro
S
Nakajima
Sachiko
S
Wang
Jun
J
Kondo
Jumpei
J
Ishii
Shuji
S
Yoshio
Toshiyuki
T
Irie
Takanobu
T
Nishida
Tsutomu
T
Kakiuchi
Yoshimi
Y
Yasumaru
Masakazu
M
Yoshihara
Harumasa
H
Kanto
Tatsuya
T
Tsujii
Masahiko
M
Tsuji
Shingo
S
Hayashi
Norio
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000378:metabolism* / Q000628:therapy; D005260:Female; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007937:Leukapheresis; D008297:Male; D008875:Middle Aged; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D007476:Ionophores; D012333:RNA, Messenger; D012097:Repressor Proteins; D015759:Ionomycin; C432966:ITCH protein, human; D050721:Proto-Oncogene Proteins c-cbl; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases