Induction of 4-1BB (CD137) expression by DNA damaging agents in human T lymphocytes.
4-1BB(CD137) is a member of the tumour necrosis factor receptor superfamily and is expressed on activated T cells, monocytes and natural killer (NK) cells. The interaction of 4-1BB and 4-1BB ligand provides a costimulatory signal leading to T-cell activation. The expression of 4-1BB has been known to be activation dependent. Interestingly, we found that expression of 4-1BB increased in human peripheral blood mononuclear cells after exposure to mitomycin C. Thus, we tested whether the treatment with other DNA-damaging agents, such as doxorubicin, bleomycin, and gamma-irradiation, could induce 4-1BB expression. The data indicated that 4-1BB expression increased dose-dependently by these agents reaching maximum at 2-3 days after the exposure. We found that the major 4-1BB-expressing population was CD3+ T cells, although a moderate number of CD14+ cells and a few NKB1+ cells also expressed 4-1BB. The levels of 4-1BB expression induced by anticancer drugs, were relatively lower than that induced by CD3 ligation. Interestingly, at subcytotoxic concentrations, doxorubicin and bleomycin considerably enhanced 4-1BB expression induced by CD3 ligation in CEM cells. The ligation of the damage-induced 4-1BB by monoclonal antibody enhanced the viability and proliferating capacity of the cells. In conclusion, the expression of 4-1BB might be one of the cellular responses of the immune cells against various genotoxic stresses.
Kim
Kwang-Mi
KM
College of Pharmacy and College of Medicine, Seoul National University, Seoul 151-742, Korea.
Kim
Ho Won
HW
Kim
Jae-Ouk
JO
Baek
Kyoung-Min
KM
Kim
Joong Gon
JG
Kang
Chang-Yuil
CY
D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics*; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D005720:Gamma Rays; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000528:radiation effects; D012333:RNA, Messenger / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
D015703:Antigens, CD; D000970:Antineoplastic Agents; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D001761:Bleomycin; D016685:Mitomycin; D004317:Doxorubicin