title: Apoptosis of murine lupus T cells induced by the selective cyclooxygenase-2 inhibitor celecoxib: molecular mechanisms and therapeutic potential.
abstract: Upregulation of cyclooxygenase (COX)-2 in T cells from patients with systemic lupus erythematosus (SLE) is associated with their resistance to functional inactivation (anergy) and to activation-induced cell death through apoptosis. It has been demonstrated that celecoxib, a selective COX-2 inhibitor, can enhance apoptosis of human lupus T cells. The present study was undertaken to investigate whether COX-2 expression is also upregulated in T cells from the lupus-prone BXBS strain of mice and if murine lupus is modified by celecoxib. COX-2 expression was detected in splenic T cells from 6 month-old male BXSB mice (murine lupus T cells) but not in T cells from 2 month-old male or 6-month-old female BXSB or in 6-month-old male C57BL/6 mice, indicating a strong correlation between COX-2 expression in T cells and lupus manifestation in mice. Celecoxib treatment induced apoptosis of murine lupus T cells in vitro, which was inhibited by z-VAD-fmk, a pan-caspase inhibitor. In the murine lupus T cells treated with celecoxib, procaspases 3 and 9, but not procaspase 8, were activated. In addition, celecoxib treatment decreased the mitochondrial membrane potential of murine lupus T cells. These data combine to suggest that celecoxib mainly uses the mitochondrial pathway rather than FADD pathway to trigger apoptosis of COX-2 expressing murine lupus T cells. Intragastric administration of celecoxib (40 mg/kg/day for 60 days) in 6-month-old male BXSB mice effectively limited the production of serum antibodies against dsDNA. Our data suggest that celecoxib may have a beneficial effect in treating autoimmune diseases such as SLE through inducing apoptosis of autoreactive T cells.
authors.affiliation: Department of Immunology, Peking University Health Science Center, Peking University, Beijing 100083, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lv
authors.initials: L
authors.lastname: Ping
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Gao
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D000068579:Celecoxib; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008928:Mitochondria / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000974:Antibodies, Antinuclear; D052246:Cyclooxygenase 2 Inhibitors; D007074:Immunoglobulin G; D011720:Pyrazoles; D013449:Sulfonamides; D020169:Caspases; D000068579:Celecoxib