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Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-κB
A.Z. Badrichani, … , F.H. Bach, C. Ferran
A.Z. Badrichani, … , F.H. Bach, C. Ferran
Published February 15, 1999
Citation Information: J Clin Invest. 1999;103(4):543-553. https://doi.org/10.1172/JCI2517.
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Bcl-2 and Bcl-XL serve an anti-inflammatory function in endothelial cells through inhibition of NF-κB

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Abstract

To maintain the integrity of the vascular barrier, endothelial cells (EC) are resistant to cell death. The molecular basis of this resistance may be explained by the function of antiapoptotic genes such as bcl family members. Overexpression of Bcl-2 or Bcl-XL protects EC from tumor necrosis factor (TNF)–mediated apoptosis. In addition, Bcl-2 or Bcl-XL inhibits activation of NF-κB and thus upregulation of proinflammatory genes. Bcl-2–mediated inhibition of NF-κB in EC occurs upstream of IκBα degradation without affecting p65-mediated transactivation. Overexpression of bcl genes in EC does not affect other transcription factors. Using deletion mutants of Bcl-2, the NF-κB inhibitory function of Bcl-2 was mapped to bcl homology domains BH2 and BH4, whereas all BH domains were required for the antiapoptotic function. These data suggest that Bcl-2 and Bcl-XL belong to a cytoprotective response that counteracts proapoptotic and proinflammatory insults and restores the physiological anti-inflammatory phenotype to the EC. By inhibiting NF-κB without sensitizing the cells (as with IκBα) to TNF-mediated apoptosis, Bcl-2 and Bcl-XL are prime candidates for genetic engineering of EC in pathological conditions where EC loss and unfettered activation are undesirable.

Authors

A.Z. Badrichani, D.M. Stroka, G. Bilbao, D.T. Curiel, F.H. Bach, C. Ferran

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Figure 3

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(a and b) Bcl-2 or Bcl-XL expression in BAEC prevents the induction of a...
(a and b) Bcl-2 or Bcl-XL expression in BAEC prevents the induction of an NF-κB reporter after TNF, LPS, and PMA stimulation without interfering with (c) p65-mediated transactivation, in contrast with (d) 293 cells. (a and b) BAEC were cotransfected with 0.7 μg of pAC (a; lanes 1, 4, and 7), Bcl-2 (a; lanes 2, 5, and 8), or mBcl-XL (a; lanes 3, 6, and 9) expression plasmids along with 0.6 μg of the NF-κB reporter and 0.3 μg of β-gal reporter. Cells were stimulated with either 100 U/ml TNF (a; lanes 4–6), 100 ng/ml LPS (a; lanes 7–9), or 5 × 10–8 PMA (b; lanes 4–6). The graphs are representative of at least three experiments performed. Results are given in RLU. Error bars are ± SE. (c) BAEC were cotransfected with 0.3 μg β-gal, 0.6 μg IκBα reporter, 40 ng p65 (RelA), and 0.7 μg of either pAC (lanes 1 and 2), mBcl-2 (lanes 3 and 4), or mBcl-XL (lanes 5 and 6) expression plasmids. Overexpression of Bcl-2 or Bcl-XL does not inhibit the induction of IκBα by p65 (lanes 4 and 6 vs. lane 2). (d) 293 cells were transfected with the same plasmids with the exception of higher concentrations of the expression plasmids (1 μg). Results show that expression of Bcl-2 or Bcl-XL inhibits the ability of p65 (RelA) to induce an IκBα reporter. Data shown are representative of three experiments performed. Results are expressed in RLU. Error bars represent ± SE.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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