Bcl-2 and Bcl-X-L serve an anti-inflammatory function in endothelial tellsthrough inhibition of NF-kappa B

To maintain the integrity of the vascular barrier, endothelial cells (EC) a re resistant to cell death. The molecular basis of this resistance may be e xplained by the function of antiapoptotic genes such as bcl family members. Overexpression of Bcl-2 or Bcl-X-L protects EC from tumor necrosis factor (TNF)-mediated apoptosis. In addition, Bcl-2 or Bcl-X-L inhibits activation of NF-kappa B and thus upregulation of proinflammatory genes. Bcl-2-mediat ed inhibition of NF-kappa B in EC occurs upstream of I kappa B alpha degrad ation without affecting p65-mediated transactivation. Overexpression of bcl genes in EC does not affect other transcription factors. Using deletion mu tants of Bcl-2, the NF-kappa B inhibitory function of Bcl-2 nas mapped to b cl homology domains BH2 and BH4, whereas all BH domains were required for t he antiapoptotic function. These data suggest that Bcl-2 and Bcl-X-L belong to a cytoprotective response that counteracts proapoptotic and proinflamma tory insults and restores the physiological anti-inflammatory phenotype to the EC. By inhibiting NF-kappa B without sensitizing the cells (as with I k appa B alpha) to TNF-mediated apoptosis, Bcl-2 and Bcl-X-L are prime candid ates for genetic engineering of EC in pathological conditions where EC loss and unfettered activation are undesirable.