CD40 and its ligand regulate pleiotropic biological responses, includingcell proliferation, differentiation, and apoptosis. In manyinflammatory lung diseases, tissue damage by environmental orendogenous oxidants plays a major role in disease pathogenesis.As the epithelial barrier is a major target for these oxidants, wepostulated that CD40, the expression of which is increased inasthma, plays a role in the regulation of apoptosis of bronchialepithelial cells exposed to oxidants. Using 16HBE 14o cells exposedto oxidant stress, we found that ligation of CD40 (inducedby G28-5 monoclonal antibodies) enhanced cell survival and increasedthe number of cells in G2/M (interphase between DNAsynthesis and mitosis) of the cell cycle. This was associated withNF- B and activator protein–1 activation and increased expressionof the inhibitor of apoptosis, c-IAP1. However, oxidant stress–inducedapoptosiswas found to be caspase- and calpain-independent implicatingCD40 ligation as a regulator of caspase-independent cell death.This was confirmed by the demonstration that CD40 ligation preventedmitochondrial release and nuclear translocation of apoptosisinducing factor. In conclusion, we demonstrate a novel role forCD40 as a regulator of epithelial cell survival against oxidant stress.Furthermore, we have identified, for the first time, an endogenousinhibitory pathway of caspase-independent cell death.