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Carbon monoxide activates NF-kappaB via ROS generation and Akt pathways to protect against cell death of hepatocytes.
Am J Physiol Gastrointest Liver Physiol. 2008 Jul; 295(1):G146-G152.AJ

Abstract

Heme oxygenase overexpression or exogenous carbon monoxide (CO) protects against hepatocyte apoptosis and fulminant hepatitis. The prevention of hepatocyte apoptosis by CO has been shown to require activation of NF-kappaB. The purpose of these investigations was to determine the mechanism of CO-induced hepatocyte NF-kappaB activation and protection against apoptosis. Primary rat or mouse hepatocytes and Hep3B cells were utilized. CO exposure was performed at 250 parts per million. Main outcome measures included cell viability, reactive oxygen species (ROS) generation, and changes in the levels of the intracellular antioxidants glutathione and ascorbate. Western blotting was performed for phospho-Akt, total Akt, and IkappaBalpha. NF-kappaB activation was determined by electrophoretic mobility shift assay and luciferase reporter assays. We found that CO treatment of hepatocytes prevents spontaneous apoptosis and leads to an increase in ROS production in association with Akt phosphorylation and IkappaB degradation. CO did not increase ROS production in respiration-deficient (rho0) Hep3B cells. Both Akt phosphorylation and IkappaB degradation can be inhibited by the addition of antioxidants. Furthermore, CO-induced NF-kappaB activation is reversed by phosphatidylinositol 3-kinase (PI3-K) inhibitor (LY294002) or antioxidants. Additionally, prevention of spontaneous hepatocyte apoptosis by CO is reversed by PI3-K inhibition and antioxidants. In conclusion, these data implicate a survival pathway of CO-induced ROS, Akt phosphorylation, and NF-kappaB activation in cultured hepatocytes. This pathway may prove to be important in maintenance of hepatic function in both physiological and pathophysiological conditions.

Authors+Show Affiliations

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18497334

Citation

Kim, Hoe Suk, et al. "Carbon Monoxide Activates NF-kappaB Via ROS Generation and Akt Pathways to Protect Against Cell Death of Hepatocytes." American Journal of Physiology. Gastrointestinal and Liver Physiology, vol. 295, no. 1, 2008, pp. G146-G152.
Kim HS, Loughran PA, Rao J, et al. Carbon monoxide activates NF-kappaB via ROS generation and Akt pathways to protect against cell death of hepatocytes. Am J Physiol Gastrointest Liver Physiol. 2008;295(1):G146-G152.
Kim, H. S., Loughran, P. A., Rao, J., Billiar, T. R., & Zuckerbraun, B. S. (2008). Carbon monoxide activates NF-kappaB via ROS generation and Akt pathways to protect against cell death of hepatocytes. American Journal of Physiology. Gastrointestinal and Liver Physiology, 295(1), G146-G152. https://doi.org/10.1152/ajpgi.00105.2007
Kim HS, et al. Carbon Monoxide Activates NF-kappaB Via ROS Generation and Akt Pathways to Protect Against Cell Death of Hepatocytes. Am J Physiol Gastrointest Liver Physiol. 2008;295(1):G146-G152. PubMed PMID: 18497334.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbon monoxide activates NF-kappaB via ROS generation and Akt pathways to protect against cell death of hepatocytes. AU - Kim,Hoe Suk, AU - Loughran,Patricia A, AU - Rao,Jayashree, AU - Billiar,Timothy R, AU - Zuckerbraun,Brian S, Y1 - 2008/05/22/ PY - 2008/5/24/pubmed PY - 2008/9/10/medline PY - 2008/5/24/entrez SP - G146 EP - G152 JF - American journal of physiology. Gastrointestinal and liver physiology JO - Am J Physiol Gastrointest Liver Physiol VL - 295 IS - 1 N2 - Heme oxygenase overexpression or exogenous carbon monoxide (CO) protects against hepatocyte apoptosis and fulminant hepatitis. The prevention of hepatocyte apoptosis by CO has been shown to require activation of NF-kappaB. The purpose of these investigations was to determine the mechanism of CO-induced hepatocyte NF-kappaB activation and protection against apoptosis. Primary rat or mouse hepatocytes and Hep3B cells were utilized. CO exposure was performed at 250 parts per million. Main outcome measures included cell viability, reactive oxygen species (ROS) generation, and changes in the levels of the intracellular antioxidants glutathione and ascorbate. Western blotting was performed for phospho-Akt, total Akt, and IkappaBalpha. NF-kappaB activation was determined by electrophoretic mobility shift assay and luciferase reporter assays. We found that CO treatment of hepatocytes prevents spontaneous apoptosis and leads to an increase in ROS production in association with Akt phosphorylation and IkappaB degradation. CO did not increase ROS production in respiration-deficient (rho0) Hep3B cells. Both Akt phosphorylation and IkappaB degradation can be inhibited by the addition of antioxidants. Furthermore, CO-induced NF-kappaB activation is reversed by phosphatidylinositol 3-kinase (PI3-K) inhibitor (LY294002) or antioxidants. Additionally, prevention of spontaneous hepatocyte apoptosis by CO is reversed by PI3-K inhibition and antioxidants. In conclusion, these data implicate a survival pathway of CO-induced ROS, Akt phosphorylation, and NF-kappaB activation in cultured hepatocytes. This pathway may prove to be important in maintenance of hepatic function in both physiological and pathophysiological conditions. SN - 0193-1857 UR - https://www.unboundmedicine.com/medline/citation/18497334/Carbon_monoxide_activates_NF_kappaB_via_ROS_generation_and_Akt_pathways_to_protect_against_cell_death_of_hepatocytes_ L2 - https://journals.physiology.org/doi/10.1152/ajpgi.00105.2007?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -