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Cyclophosphamide enhances TNF-alpha-induced apoptotic cell death in murine vascular endothelial cell
Toshio Ohtani1, Tomoyuki Nakamura, Ken-Ichi Toda
1Department of Dermatology, Wakayama Medical University, 811-1 Kimi-idera, Wakayama, Japan. tossan@wakayama-med.ac.jp
Abstract:
Cyclophosphamide (CPA) is one of the therapeutic agents for systemic inflammatory disorders. In murine dermal endothelial cells (F-2), 4-hydroxycyclophosphamide (4-HC), which is active metabolite of CPA, enhanced TNF-alpha-induced DNA fragmentation. In addition, 4-HC was shown to elevate TNF-alpha-induced caspase-3 activation. Caspase-8 activation was identified by the treatment of TNF-alpha, whereas 4-HC was no effect. In contrast, only when treated with 4-HC, caspase-9 activation and the increase in the intracellular expression of Bax were detected. These results suggest that CPA may sensitize endothelial cells to TNF-alpha-induced apoptosis through a mitochondria-dependent pathway and clinically may contribute to the limitation of inflammatory process.
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