Focal Adhesion Kinase Activity and Localization is Critical for TNF-α-Induced Nuclear Factor-κB Activation

While sustained nuclear factor-kappa B (NF-kappa B) activation is critical for proinflammatory molecule expression, regulators of NF-kappa B activity during chronic inflammation are not known. We investigated the role of focal adhesion kinase (FAK) on sustained NF-kappa B activation in tumor necrosis factor-alpha (TNF-alpha)-stimulated endothelial cells (ECs) both in vitro and in vivo. We found that FAK inhibition abolished TNF-alpha-mediated sustained NF-kappa B activity in ECs by disrupting formation of TNF-alpha receptor complex-I (TNFRC-I). Additionally, FAK inhibition diminished recruitment of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and the inhibitor of NF-kappa B (I kappa B) kinase (IKK) complex to TNFRC-I, resulting in elevated stability of I kappa B alpha protein. In mice given TNF-alpha, pharmacological and genetic FAK inhibition blocked TNF-alpha-induced IKK-NF-kappa B activation in aortic ECs. Mechanistically, TNF-alpha activated and redistributed FAK from the nucleus to the cytoplasm, causing elevated IKK-NF-kappa B activation. On the other hand, FAK inhibition trapped FAK in the nucleus of ECs even upon TNF-alpha stimulation, leading to reduced IKK-NF-kappa B activity. Together, these findings support a potential use for FAK inhibitors in treating chronic inflammatory diseases.

Automated summary

The study reveals that focal adhesion kinase (FAK) plays a crucial role in regulating sustained NF-kappa B activation in endothelial cells (ECs) stimulated by tumor necrosis factor-alpha (TNF-alpha). Inhibition of FAK disrupts the formation of TNF-alpha receptor complex-I (TNFRC-I) and diminishes recruitment of downstream proteins, leading to reduced NF-kappa B activity. Targeting FAK may hold promise for treating chronic inflammatory diseases.