CD40 Ligation Protects Bronchial Epithelium against Oxidant-Induced Caspase-Independent Cell Death

CD40 and its ligand regulate pleiotropic biological responses, including cell proliferation, differentiation, and apoptosis. In many inflammatory lung diseases, tissue damage by environmental or endogenous oxidants plays a major role in disease pathogenesis. As the epithelial barrier is a major targ...

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Veröffentlicht in:American journal of respiratory cell and molecular biology 2006-08, Vol.35 (2), p.155-164
Hauptverfasser: Merendino, Anna M, Bucchieri, Fabio, Gagliardo, Rosalia, Daryadel, Arezoo, Pompeo, Flora, Chiappara, Giuseppina, Santagata, Roberta, Bellia, Vincenzo, David, Sabrina, Farina, Felicia, Davies, Donna E, Simon, Hans-Uwe, Vignola, Antonio M
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Sprache:eng
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Zusammenfassung:CD40 and its ligand regulate pleiotropic biological responses, including cell proliferation, differentiation, and apoptosis. In many inflammatory lung diseases, tissue damage by environmental or endogenous oxidants plays a major role in disease pathogenesis. As the epithelial barrier is a major target for these oxidants, we postulated that CD40, the expression of which is increased in asthma, plays a role in the regulation of apoptosis of bronchial epithelial cells exposed to oxidants. Using 16HBE 14o- cells exposed to oxidant stress, we found that ligation of CD40 (induced by G28-5 monoclonal antibodies) enhanced cell survival and increased the number of cells in G2/M (interphase between DNA synthesis and mitosis) of the cell cycle. This was associated with NF-kappaB and activator protein-1 activation and increased expression of the inhibitor of apoptosis, c-IAP1. However, oxidant stress-induced apoptosis was found to be caspase- and calpain-independent implicating CD40 ligation as a regulator of caspase-independent cell death. This was confirmed by the demonstration that CD40 ligation prevented mitochondrial release and nuclear translocation of apoptosis inducing factor. In conclusion, we demonstrate a novel role for CD40 as a regulator of epithelial cell survival against oxidant stress. Furthermore, we have identified, for the first time, an endogenous inhibitory pathway of caspase-independent cell death.
ISSN:1044-1549
1535-4989
DOI:10.1165/rcmb.2005-0433OC