Endothelial cell activation by antiphospholipid antibodies is modulated by Kruppel-like transcription factors

Antiphospholipid syndrome is characterized by thrombosis and/or recurrent pregnancy loss in the presence of antiphospholipid antibodies (APLAs). The majority of APLAs are directed against phospholipid-binding proteins, particularly beta(2)-glycoprotein I (beta(2)GPI). Anti-beta(2)GPI antibodies activate endothelial cells in a beta(2)-GPI-dependent manner through a pathway that involves NF-kappa B. Kruppel-like factors (KLFs) play a critical role in regulating the endothelial response to inflammatory stimuli. We hypothesized that activation of endothelial cells by APLA/anti-beta(2)GPI antibodies might be associated with decreased expression of KLFs, which in turn might facilitate cellular activation mediated through NF-kappa B. Our experimental results confirmed this hypothesis, demonstrating markedly decreased expression of KLF2 and KLF4 after incubation of cells with APLA/anti-beta(2)GPI antibodies. Restoration of KLF2 or KLF4 levels inhibited NF-kappa B transcriptional activity and blocked APLA/anti-beta(2)GPI-mediated endothelial activation despite NF-kappa B p65 phosphorylation. Chromatin immunoprecipitation analysis demonstrated that inhibition of NF-kappa B transcriptional activity by KLFs reflects sequestration of the cotranscriptional activator CBP/p300, making this cofactor unavailable to NF-kappa B. These findings suggest that the endothelial response to APLA/anti-beta(2)GPI antibodies reflects competition between KLFs and NF-kappa B for their common cofactor, CBP/p300. Taken together, these observations are the first to implicate the KLFs as novel participants in the endothelial proinflammatory response to APLA/anti-beta(2)GPI antibodies. (Blood. 2011; 117(23): 6383-6391)