CD40 ligation protects bronchial epithelium against oxidant-induced caspase-independent cell death

Merendino, Anna Maria, Bucchieri, Fabio, Gagliardo, Rosalia, Daryadel, Arezoo, Pompeo, Flora, Chiappara, Giuseppina, Santagata, Roberta, Bellia, Vincenzo, David, Sabrina, Farina, Felicia, Davies, Donna E., Simon, Hans Uwe and Vignola, Antonio M. (2006) CD40 ligation protects bronchial epithelium against oxidant-induced caspase-independent cell death. American Journal of Respiratory Cell and Molecular Biology, 35 (2), 155-164. (doi:10.1165/rcmb.2005-0433OC).

Abstract

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-κB 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.

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Contributors

Author: Donna E. Davies

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