Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-κB-dependent PTEN activation

Bysani Chandrasekar, Anthony J. Valente, Gregory L. Freeman, Lenin Mahimainathan, Srinivas Mummidi

Research output: Contribution to journalArticle

50 Scopus citations


The tumor suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) antagonizes the pro-survival signaling of Akt and promotes cell death. Previously, we demonstrated that IL-18 induced apoptosis in human cardiac microvascular endothelial cells (HCMEC). Here we have investigated the role of PTEN in this response. Our results demonstrate that IL-18 reduced phospho-Akt and bcl-2 levels, stimulated NF-κB activation, and induced PTEN-promoter-reporter activity, mRNA expression, and protein levels in HCMEC. IL-18-mediated PTEN transcription was enhanced by ectopic expression of wild type p65, but inhibited by dominant negative (dn) IκB-α, dnp65, and dnIKKβ. Furthermore, overexpression of constitutively active Akt and wild type bcl-2 blocked IL-18-mediated cell death. While forced expression of PTEN potentiated, expression of catalytically inactive PTEN attenuated IL-18-mediated cell death. IL-18-induced activation of NF-κB and PTEN upregulation were mediated by p38MAPK. Together, these studies demonstrate a novel signal transduction pathway involving p38MAPK-NF-κB-PTEN in IL-18-mediated HCMEC death, and identify IL-18 as potential therapeutic target to inhibit or reduce myocardial inflammation and injury.

Original languageEnglish (US)
Pages (from-to)956-963
Number of pages8
JournalBiochemical and Biophysical Research Communications
Issue number3
StatePublished - Jan 20 2006



  • Apoptosis
  • Bcl-2
  • Endothelial cells
  • IL-18
  • Interleukins
  • PTEN
  • Signal transduction
  • p38MAPK

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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