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FLICE-Like Inhibitory Protein (FLIP) Protects Against Apoptosis and Suppresses NF-κB Activation Induced by Bacterial Lipopolysaccharide

https://doi.org/10.1016/S0002-9440(10)63400-1Get rights and content

Bacterial lipopolysaccharide (LPS) via its activation of Toll-like receptor-4 contributes to much of the vascular injury/dysfunction associated with gram-negative sepsis. Inhibition of de novo gene expression has been shown to sensitize endothelial cells (EC) to LPS-induced apoptosis, the onset of which correlates with decreased expression of FLICE-like inhibitory protein (FLIP). We now have data that conclusively establish a role for FLIP in protecting EC against LPS-induced apoptosis. Overexpression of FLIP protected against LPS-induced apoptosis, whereas down-regulation of FLIP using antisense oligonucleotides sensitized EC to direct LPS killing. Interestingly, FLIP overexpression suppressed NF-κB activation induced by LPS, but not by phorbol ester, suggesting a specific role for FLIP in mediating LPS activation. Conversely, mouse embryo fibroblasts (MEF) obtained from FLIP −/− mice showed enhanced LPS-induced NF-κB activation relative to those obtained from wild-type mice. Reconstitution of FLIP−/− MEF with full-length FLIP reversed the enhanced NF-κB activity elicited by LPS in the FLIP −/− cells. Changes in the expression of FLIP had no demonstrable effect on other known LPS/Tlr-4-activated signaling pathways including the p38, Akt, and Jnk pathways. Together, these data support a dual role for FLIP in mediating LPS-induced apoptosis and NF-κB activation.

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Supported by United States Department of Agriculture, Cooperative State Research, Education and Extension Research-National Research Initiative Grant 2003–35204-13484 (D.D.B.) and National Institutes of Health Grants GM42686 (R.K.W.) and HL18645 (J.M.H.).

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