CD137 activation abrogates granulocyte-macrophage colony-stimulating factor-mediated anti-apoptosis in neutrophils

CD137 (ILA / 4-1BB) is a member of the TNF / NGF receptor family, and has previously been suggested to be involved in T cell activation and differentiation. Here, we demonstrate that blood neutrophils from control individuals and patients with cystic fibrosis express CD137 mRNA and surface protein. In contrast, lung neutrophils derived from patients with cystic fibrosis did not express detectable CD137 levels. Such CD137-deficient neutrophils could also be generated from normal neutrophils by TNF-alpha stimulation in vitro. TNF-alpha was found to be highly expressed in epithelial cells from cystic fibrosis but not normal lungs, suggesting that TNF-alpha might account for reduced neutrophil CD137 levels under inflammatory conditions in vivo. To investigate whether CD137 is involved in the regulation of apoptosis, neutrophils were activated with functional anti-CD137 antibody in the presence or absence of different neutrophil survival factors in vitro. Activation of CD137 abrogated GM-CSF-mediated anti-apoptosis in normal but not in CD137-deficient neutrophils. Moreover, G-CSF- and IFN-gamma-mediated neutrophil anti-apoptosis was not affected by anti-CD137 antibody treatment. In conclusion, these data suggest that CD137 activation may limit GM-CSF-mediated anti-apoptosis of neutrophils. The absence of this anti-inflammatory mechanism in inflammatory responses might be associated with massive neutrophil accumulation and consequent tissue damage.