Enhanced expression of Fas-associated death domain-like IL-1-converting enzyme (FLICE)-inhibitory protein induces resistance to Fas-mediated apoptosis in activated mast cells

Mast cells play a critical role in host immune responses and are implicated in the pathogenesis of allergic inflammation, Though mouse mast cell line MC/9 expresses cell surface Fas Ag and is sensitive to Fas-induced apoptosis, activated MC/9 cells are resistant to Fas-induced cell death by cross-linking of Fc epsilon RI or Fc gammaR, Fas-associated death domain-like IL-l-converting enzyme (FLICE)-inhibitory protein (FLIP), a caspase-8 inhibitor that lacks the cisteine domain, is one of the negative regulators of receptor-mediated apoptosis, In this report, we show that activation of mast cells by cross-linking of Fc epsilon RI or Fc gammaR can induce enhanced expression of FLIP and consequently a resistance to Fas-induced apoptosis, although the expression level of Fas Ag is not changed, Addition of antisense oligonucleotide for FLIP prevents resistance to Fab-induced apoptosis of activated mast cells, suggesting that endogenous FLIP inhibits Fas-mediated apoptosis in activated mast cells. Thus, the enhanced expression of FLIP in activated mast cells contributes to the resistance to Fas-induced apoptosis, which may result in the development and prolongation of allergic inflammation.