TY - JOUR
T1 - Resistance of Crohn's disease T cells to multiple apoptotic signals is associated with a Bcl-2/Bax mucosal imbalance
AU - Ina, Kenji
AU - Itoh, Jugoh
AU - Fukushima, Kouhei
AU - Kusugami, Kazuo
AU - Yamaguchi, Takeo
AU - Kyokane, Kazuhiro
AU - Imada, Akira
AU - Binion, David G.
AU - Musso, Alessandro
AU - West, Gail A.
AU - Dobrea, George M.
AU - McCormick, Thomas S.
AU - Lapetina, Eduardo G.
AU - Levine, Alan D.
AU - Ottaway, Clifford A.
AU - Fiocchi, Claudio
PY - 1999/7/15
Y1 - 1999/7/15
N2 - Crohn's disease (CD) is a condition characterized by excessive numbers of activated T cells in the mucosa. We investigated whether a defect in apoptosis could prolong T cell survival and contribute to their accumulation in the mucosa. Apoptotic, Bcl-2+, and Bax+ cells in tissue sections were detected by the TUNEL method and immunohistochemistry. T cell apoptosis was induced by IL-2 deprivation, Fas Ag ligation, and exposure to TNF-α and nitric oxide. TUNEL+ leukocytes were few in control, CD, and ulcerative colitis (UC) mucosa, with occasional CD68+ and myeloperoxidase+, but no CD45RO+, apoptotic cells. Compared with control and UC, CD T cells grew remarkably more in response to IL-2 and were significantly more resistant to IL-2 deprivation-induced apoptosis. CD T cells were also more resistant to Fas- and nitric oxide-mediated apoptosis, whereas TNF-α failed to induce cell death in all groups. Compared with control, CD mucosa contained similar numbers of Bel-2+, but fewer Bax+, cells, while UC mucosa contained fewer Bel-2+, but more Bax+, cells. Hence, the Bel-2/Bax ratio was significantly higher in CD and lower in UC. These results indicate that CD may represent a disorder where the rate of T cell proliferation exceeds that of cell death. Insufficient T cell apoptosis may interfere with clonal deletion and maintenance of tolerance, and result in inappropriate T cell accumulation contributing to chronic inflammation.
AB - Crohn's disease (CD) is a condition characterized by excessive numbers of activated T cells in the mucosa. We investigated whether a defect in apoptosis could prolong T cell survival and contribute to their accumulation in the mucosa. Apoptotic, Bcl-2+, and Bax+ cells in tissue sections were detected by the TUNEL method and immunohistochemistry. T cell apoptosis was induced by IL-2 deprivation, Fas Ag ligation, and exposure to TNF-α and nitric oxide. TUNEL+ leukocytes were few in control, CD, and ulcerative colitis (UC) mucosa, with occasional CD68+ and myeloperoxidase+, but no CD45RO+, apoptotic cells. Compared with control and UC, CD T cells grew remarkably more in response to IL-2 and were significantly more resistant to IL-2 deprivation-induced apoptosis. CD T cells were also more resistant to Fas- and nitric oxide-mediated apoptosis, whereas TNF-α failed to induce cell death in all groups. Compared with control, CD mucosa contained similar numbers of Bel-2+, but fewer Bax+, cells, while UC mucosa contained fewer Bel-2+, but more Bax+, cells. Hence, the Bel-2/Bax ratio was significantly higher in CD and lower in UC. These results indicate that CD may represent a disorder where the rate of T cell proliferation exceeds that of cell death. Insufficient T cell apoptosis may interfere with clonal deletion and maintenance of tolerance, and result in inappropriate T cell accumulation contributing to chronic inflammation.
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M3 - Article
C2 - 10395708
AN - SCOPUS:0033565302
VL - 163
SP - 1081
EP - 1090
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 2
ER -