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Role of NF-B and PI 3-kinase/Akt in TNF--induced cytotoxicity in microvascular endothelial cells

¹Department of Medicine, University of Colorado at Denver and Health Sciences Center, Denver, Colorado; and ²First Affiliated Hospital of Kunming Medical College, Kunming, Yunnai, People's Republic of China

Submitted 6 February 2008 ; accepted in final form 10 July 2008

The interaction of tumor necrosis factor (TNF)- with the endothelium is a pivotal factor during endotoxemia. Inflammatory conditions are characterized by the activation of the transcription factor NF-B and the expression of inflammatory mediators. Previous reports indicate that inhibition of NF-B activation during sepsis may be beneficial to the microvasculature. In addition, the phosphatidylinositol-3-kinase/Akt signaling pathway (PI3-kinase/Akt) has been shown to be cytoprotective. In this study, we examined the effect of inhibition of NF-B and PI3-kinase/Akt on cell viability, cytokine production, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) generation by TNF--treated cultured microvascular endothelial cells. TNF- induced significant cytotoxicity and was associated with increased inflammatory cytokines and NO and increased expression of iNOS. The NF-B inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented these increases and significantly attenuated the TNF--induced cytotoxicity. TNF- also caused PI3-kinase/Akt activation, which was further increased by PDTC and prevented by the PI3-kinase inhibitor, LY294002. Inhibition of PI3-kinase/Akt also significantly potentiated TNF--mediated cytotoxicity. LY294002 treatment resulted in the appearance of increased apoptosis, compatible with the known anti-apoptotic properties of PI3-kinase/Akt. The present results therefore demonstrate a cytotoxic effect of TNF- in microvascular endothelial cells which can be attenuated by NF-B inhibition. In addition, PI3-kinase/Akt activation during TNF- exposure may represent a compensatory anti-necrotic and anti-apoptotic pathway. The cytoprotective effects of NF-B inhibition and PI3-kinase/Akt activation may have potential implications in the treatment of endotoxemia and septic shock.

endotoxemia; sepsis; cell culture; PDTC; LY294002

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