c-FLIP Protects Eosinophils from TNF-α-Mediated Cell Death In Vivo

Understanding the signals that regulate eosinophil survival and death is critical to developing new treatments for asthma, atopy, and gastrointestinal disease. Previous studies suggest that TNF-alpha stimulation protects eosinophils from apoptosis, and this TNF-alpha-mediated protection is mediated by the upregulation of an unknown protein by NF-kappa B. Here, we show for the first time that eosinophils express the caspase 8-inhibitory protein c-FLIP, and c-FLIP expression is upregulated upon TNF-alpha stimulation. Considering that c-FLIP expression is regulated by NF-kappa B, we hypothesized that c-FLIP might serve as the "molecular switch'' that converts TNFRI activation to a pro-survival signal in eosinophils. Indeed, we found that one c-FLIP isoform, c-FLIPL, is required for mouse eosinophil survival in the presence of TNF-alpha both in vitro and in vivo. Importantly, our results suggest c-FLIP as a potential therapeutic target for the treatment of eosinophil-mediated disease.