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• W1982509301 abstract "BackgroundEndothelial thrombomodulin (TM) is critically involved in anticoagulation, anti‐inflammation, cytoprotection and normal fetal development. Tumor necrosis factor alpha (TNFα) suppresses TM expression.ObjectiveTNFα has been shown to down‐regulate TM partly via activation of nuclear factor kappa B (NF‐κB). However, because the TM promoter lacks an NF‐κB binding site, the direct involvement of NF‐κB has been controversial. We investigated the role of the upstream regulatory serine kinase, inhibitory kappa‐B kinase‐β (IKKβ), in TM expression and function with or without TNFα treatment.MethodsInhibition of IKKβ was achieved by specific chemical inhibitors, siRNA or shRNA. TM expression was assessed by qRT‐PCR, Western blot, flow cytometry, luciferase reporter assay and chromatin immune‐precipitation (ChIP) assay. TM function was estimated by generation of activated protein C (APC). NF‐κB activation was determined by immunocytochemistry.Results and conclusionsIKKβ inhibition increased TM expression and function, and attenuated TNFα‐mediated TM down‐regulation. In contrast, inhibition of downstream canonical NF‐κB protein family members p50 and p65 (RelA) failed to up‐regulate TM expression and did not affect IKKβ inhibition‐mediated TM over‐expression. However, knockdown of cRel and RelB, family members of the canonical and non‐canonical NF‐κB pathway, respectively, resulted in TM over‐expression. IKKβ inhibition caused over‐expression, increased promoter activity and enhanced binding of Krüppel‐like factor 2 (Klf2) to the TM promoter, which positively regulates TM expression. Finally, knockdown of Klf2 completely attenuated IKKβ inhibition‐mediated TM up‐regulation. We conclude that IKKβ regulates TM in a Klf2‐dependent manner." @default.
• W1982509301 created "2016-06-24" @default.
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• W1982509301 date "2014-09-01" @default.
• W1982509301 modified "2023-10-18" @default.
• W1982509301 title "IKKβ regulates endothelial thrombomodulin in a Klf2‐dependent manner" @default.
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• W1982509301 doi "https://doi.org/10.1111/jth.12664" @default.
• W1982509301 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4163124" @default.
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