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Role of NF-kappaB and PI 3-kinase/Akt in TNF-alpha-induced cytotoxicity in microvascular endothelial cells.
Am J Physiol Renal Physiol. 2008 Oct; 295(4):F932-41.AJ

Abstract

The interaction of tumor necrosis factor (TNF)-alpha with the endothelium is a pivotal factor during endotoxemia. Inflammatory conditions are characterized by the activation of the transcription factor NF-kappaB and the expression of inflammatory mediators. Previous reports indicate that inhibition of NF-kappaB 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-kappaB and PI3-kinase/Akt on cell viability, cytokine production, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) generation by TNF-alpha-treated cultured microvascular endothelial cells. TNF-alpha induced significant cytotoxicity and was associated with increased inflammatory cytokines and NO and increased expression of iNOS. The NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented these increases and significantly attenuated the TNF-alpha-induced cytotoxicity. TNF-alpha 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-alpha-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-alpha in microvascular endothelial cells which can be attenuated by NF-kappaB inhibition. In addition, PI3-kinase/Akt activation during TNF-alpha exposure may represent a compensatory anti-necrotic and anti-apoptotic pathway. The cytoprotective effects of NF-kappaB inhibition and PI3-kinase/Akt activation may have potential implications in the treatment of endotoxemia and septic shock.

Authors+Show Affiliations

Department of Medicine, University of Colorado at Denver and Health Sciences Center, Box B173, 4200 E 9th Ave., Denver, CO 80262, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

18632801

Citation

Zhou, Zhu, et al. "Role of NF-kappaB and PI 3-kinase/Akt in TNF-alpha-induced Cytotoxicity in Microvascular Endothelial Cells." American Journal of Physiology. Renal Physiology, vol. 295, no. 4, 2008, pp. F932-41.
Zhou Z, Gengaro P, Wang W, et al. Role of NF-kappaB and PI 3-kinase/Akt in TNF-alpha-induced cytotoxicity in microvascular endothelial cells. Am J Physiol Renal Physiol. 2008;295(4):F932-41.
Zhou, Z., Gengaro, P., Wang, W., Wang, X. Q., Li, C., Faubel, S., Rivard, C., & Schrier, R. W. (2008). Role of NF-kappaB and PI 3-kinase/Akt in TNF-alpha-induced cytotoxicity in microvascular endothelial cells. American Journal of Physiology. Renal Physiology, 295(4), F932-41. https://doi.org/10.1152/ajprenal.00066.2008
Zhou Z, et al. Role of NF-kappaB and PI 3-kinase/Akt in TNF-alpha-induced Cytotoxicity in Microvascular Endothelial Cells. Am J Physiol Renal Physiol. 2008;295(4):F932-41. PubMed PMID: 18632801.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of NF-kappaB and PI 3-kinase/Akt in TNF-alpha-induced cytotoxicity in microvascular endothelial cells. AU - Zhou,Zhu, AU - Gengaro,Patricia, AU - Wang,Wei, AU - Wang,Xue-qing, AU - Li,Chunling, AU - Faubel,Sarah, AU - Rivard,Christopher, AU - Schrier,Robert W, Y1 - 2008/07/16/ PY - 2008/7/18/pubmed PY - 2008/12/17/medline PY - 2008/7/18/entrez SP - F932 EP - 41 JF - American journal of physiology. Renal physiology JO - Am J Physiol Renal Physiol VL - 295 IS - 4 N2 - The interaction of tumor necrosis factor (TNF)-alpha with the endothelium is a pivotal factor during endotoxemia. Inflammatory conditions are characterized by the activation of the transcription factor NF-kappaB and the expression of inflammatory mediators. Previous reports indicate that inhibition of NF-kappaB 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-kappaB and PI3-kinase/Akt on cell viability, cytokine production, inducible nitric oxide synthase (iNOS) expression, and nitric oxide (NO) generation by TNF-alpha-treated cultured microvascular endothelial cells. TNF-alpha induced significant cytotoxicity and was associated with increased inflammatory cytokines and NO and increased expression of iNOS. The NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), prevented these increases and significantly attenuated the TNF-alpha-induced cytotoxicity. TNF-alpha 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-alpha-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-alpha in microvascular endothelial cells which can be attenuated by NF-kappaB inhibition. In addition, PI3-kinase/Akt activation during TNF-alpha exposure may represent a compensatory anti-necrotic and anti-apoptotic pathway. The cytoprotective effects of NF-kappaB inhibition and PI3-kinase/Akt activation may have potential implications in the treatment of endotoxemia and septic shock. SN - 1931-857X UR - https://www.unboundmedicine.com/medline/citation/18632801/Role_of_NF_kappaB_and_PI_3_kinase/Akt_in_TNF_alpha_induced_cytotoxicity_in_microvascular_endothelial_cells_ L2 - https://journals.physiology.org/doi/10.1152/ajprenal.00066.2008?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -