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

摘要

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-glycoprotein I (betaGPI). Anti-betaGPI antibodies activate endothelial cells in a betaGPI-dependent manner through a pathway that involves NF-kappaB. 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-betaGPI antibodies might be associated with decreased expression of KLFs, which in turn might facilitate cellular activation mediated through NF-kappaB. Our experimental results confirmed this hypothesis, demonstrating markedly decreased expression of KLF2 and KLF4 after incubation of cells with APLA/anti-betaGPI antibodies. Restoration of KLF2 or KLF4 levels inhibited NF-kappaB transcriptional activity and blocked APLA/anti-betaGPI-mediated endothelial activation despite NF-kappaB p65 phosphorylation. Chromatin immunoprecipitation analysis demonstrated that inhibition of NF-kappaB transcriptional activity by KLFs reflects sequestration of the cotranscriptional activator CBP/p300, making this cofactor unavailable to NF-kappaB. These findings suggest that the endothelial response to APLA/anti-betaGPI antibodies reflects competition between KLFs and NF-kappaB 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-betaGPI antibodies.