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 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.
Department of Medicine, Pneumology, Physiology, and Human Nutrition, Universita' di Palermo, Ospedale V, Cervello, Via Trabucco 180, 90146 Palermo, Italy. annameren@yahoo.it
Anna M
AM
Merendino
Fabio
F
Bucchieri
Rosalia
R
Gagliardo
Arezoo
A
Daryadel
Flora
F
Pompeo
Giuseppina
G
Chiappara
Roberta
R
Santagata
Vincenzo
V
Bellia
Sabrina
S
David
Felicia
F
Farina
Donna E
DE
Davies
Hans-Uwe
HU
Simon
Antonio M
AM
Vignola
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001980:Bronchi / Q000166:cytology*; D019013:CD40 Antigens / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002472:Cell Transformation, Viral; D019610:Cytoprotection / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D016877:Oxidants / Q000494:pharmacology*; D013539:Simian virus 40 / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism
D019013:CD40 Antigens; D016877:Oxidants; D018808:Transcription Factor AP-1; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D020169:Caspases