Interleukin-18 induces human cardiac endothelial cell death via a novel signaling pathway involving NF-kappaB-dependent PTEN activation.
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-kappaB 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) IkappaB-alpha, dnp65, and dnIKKbeta. 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-kappaB and PTEN upregulation were mediated by p38MAPK. Together, these studies demonstrate a novel signal transduction pathway involving p38MAPK-NF-kappaB-PTEN in IL-18-mediated HCMEC death, and identify IL-18 as potential therapeutic target to inhibit or reduce myocardial inflammation and injury.
Chandrasekar
Bysani
B
Department of Medicine/Cardiology, The University of Texas Health Science Center, San Antonio, TX 78229, USA. chandraseka@uthscsa.edu
Valente
Anthony J
AJ
Freeman
Gregory L
GL
Mahimainathan
Lenin
L
Mummidi
Srinivas
S
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism* / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D020382:Interleukin-18; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human