title: Endothelial cell activation by antiphospholipid antibodies is modulated by Kruppel-like transcription factors.
abstract: 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 β₂-glycoprotein I (β₂GPI). Anti-β₂GPI antibodies activate endothelial cells in a β₂GPI-dependent manner through a pathway that involves NF-κB. Krüppel-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-β₂GPI antibodies might be associated with decreased expression of KLFs, which in turn might facilitate cellular activation mediated through NF-κB. Our experimental results confirmed this hypothesis, demonstrating markedly decreased expression of KLF2 and KLF4 after incubation of cells with APLA/anti-β₂GPI antibodies. Restoration of KLF2 or KLF4 levels inhibited NF-κB transcriptional activity and blocked APLA/anti-β₂GPI-mediated endothelial activation despite NF-κB p65 phosphorylation. Chromatin immunoprecipitation analysis demonstrated that inhibition of NF-κB transcriptional activity by KLFs reflects sequestration of the cotranscriptional activator CBP/p300, making this cofactor unavailable to NF-κB. These findings suggest that the endothelial response to APLA/anti-β₂GPI antibodies reflects competition between KLFs and NF-κB 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-β₂GPI antibodies.
authors.affiliation: Department of Cell Biology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Allen
authors.forename: Anne
authors.initials: A
authors.lastname: Hamik
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
authors.forename: Keith R
authors.initials: KR
authors.lastname: McCrae
mesh_terms: D000026:Abortion, Habitual / Q000276:immunology / Q000378:metabolism; D017152:Antibodies, Antiphospholipid / Q000276:immunology / Q000378:metabolism*; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000276:immunology / Q000378:metabolism*; D008297:Male; D011247:Pregnancy; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D053482:beta 2-Glycoprotein I / Q000276:immunology / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000276:immunology / Q000378:metabolism
chemical_list: D017152:Antibodies, Antiphospholipid; C096161:KLF2 protein, human; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C498143:RELA protein, human; D051996:Transcription Factor RelA; D053482:beta 2-Glycoprotein I; D050880:p300-CBP Transcription Factors