Published ahead of print on March 16, 2006, doi:10.1165/rcmb.2005-0433OC Am. J. Respir. Cell Mol. Biol., Volume 35, Number 2, August 2006, 155-164 A more recent version of this article appeared on August 1, 2006
Submitted on November 25, 2005 CD40 Ligation Protects Bronchial Epithelium Against Oxidant-induced Caspase-independent Cell DeathAnna Maria Merendino1*,1 Department of Medicine, Pneumology, Physiology, and Human Nutrition, Universita di Palermo, Palermo, Italy, 2 Department of Experimental Medicine, Section of Human Anatomy, Universita di Palermo, Palermo, Italy; Division of Infection, Inflammation and Repair, University of Southampton, Southampton, United Kingdom, 3 Institute of Biomedicine and Molecular Immunology (IBIM), Italian National Research Council (CNR), Palermo, Italy, 4 Department of Pharmacology, University of Bern, Bern, Switzerland, 5 Department of Experimental Medicine, Section of Human Anatomy, Universita di Palermo, Palermo, Italy, 6 Division of Infection, Inflammation and Repair, University of Southampton, Southampton, United Kingdom, 7 Department of Medicine, Pneumology, Physiology, and Human Nutrition, Universita di Palermo, Palermo, Italy; Institute of Biomedicine and Molecular Immunology (IBIM), Italian National Research Council (CNR), Palermo, Italy * To whom correspondence should be addressed. E-mail: annameren{at}yahoo.it.
CD40 and its ligand (CD40 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, whose expression is increased in asthma, plays a role in the regulation of apoptosis of bronchial epithelial cells exposed to oxidants. Using 16HBE 14o- bronchial epithelial cells exposed to oxidant stress, we found that ligation of CD40 (induced by G28-5 mAb) enhanced cell survival and increased the number of cells in G2/M of the cell cycle. This was associated with NF
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B and AP-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, AIF. 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.
