Document Detail


IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2-induced Bak interactions with mitofusins.
MedLine Citation:
PMID:  19168699     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Overexpression of IL-6 markedly diminishes hyperoxic lung injury, hyperoxia-induced cell death, and DNA fragmentation, and enhances Bcl-2 expression. We hypothesized that changes in the interactions between Bcl-2 family members play an important role in the IL-6-mediated protective response to oxidative stress. Consistent with this hypothesis, we found that IL-6 induced Bcl-2 expression, both in vivo and in vitro, disrupted interactions between proapoptotic and antiapoptotic factors, and suppressed H(2)O(2)-induced loss of mitochondrial membrane potential in vitro. In addition, IL-6 overexpression in mice protects against hyperoxia-induced lung mitochondrial damage. The overexpression of Bcl-2 in vivo prolonged the survival of mice exposed to hyperoxia and inhibited alveolar capillary protein leakage. In addition, apoptosis-associated DNA fragmentation was substantially reduced in these animals. This IL-6-mediated protection was lost when Bcl-2 was silenced, demonstrating that Bcl-2 is an essential mediator of IL-6 cytoprotection. Finally, Bcl-2 blocked the dissociation of Bak from mitofusin protein (Mfn) 2, and inhibited the interaction between Bak and Mfn1. Taken together, our results suggest that IL-6 induces Bcl-2 expression to perform cytoprotective functions in response to oxygen toxicity, and that this effect is mediated by alterations in the interactions between Bak and Mfns.
Authors:
Aaron B Waxman; Narasaiah Kolliputi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2009-01-23
Journal Detail:
Title:  American journal of respiratory cell and molecular biology     Volume:  41     ISSN:  1535-4989     ISO Abbreviation:  Am. J. Respir. Cell Mol. Biol.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-09-16     Completed Date:  2009-10-20     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  8917225     Medline TA:  Am J Respir Cell Mol Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  385-96     Citation Subset:  IM    
Affiliation:
Pulmonary Critical Care Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 148, Boston, MA 02114, USA. abwaxman@partners.org.
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MeSH Terms
Descriptor/Qualifier:
Acute Lung Injury / etiology,  physiopathology,  prevention & control
Animals
Apoptosis Regulatory Proteins / metabolism
Cells, Cultured / drug effects,  metabolism
Endothelial Cells / drug effects,  metabolism
GTP Phosphohydrolases / metabolism*
Humans
Hyperoxia / drug therapy*,  physiopathology
Interleukin-6 / genetics,  pharmacology,  physiology*
Lipid Peroxidation / drug effects
Lung / drug effects*,  metabolism,  pathology
Membrane Proteins / metabolism*
Membrane Transport Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria / drug effects*,  metabolism
Mitochondrial Membrane Transport Proteins
Mitochondrial Proteins / metabolism*
Oxidative Stress / drug effects*,  physiology
Oxygen / toxicity*
Protein Interaction Mapping
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors,  biosynthesis,  genetics,  physiology*
RNA, Small Interfering / pharmacology
Recombinant Fusion Proteins / physiology
bcl-2 Homologous Antagonist-Killer Protein / metabolism*
Grant Support
ID/Acronym/Agency:
R01HL074859/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BAK1 protein, human; 0/Bak1 protein, mouse; 0/IL6 protein, human; 0/Interleukin-6; 0/Membrane Proteins; 0/Membrane Transport Proteins; 0/Mitochondrial Membrane Transport Proteins; 0/Mitochondrial Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Small Interfering; 0/Recombinant Fusion Proteins; 0/bcl-2 Homologous Antagonist-Killer Protein; 7782-44-7/Oxygen; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/MFN2 protein, human; EC 3.6.1.-/Mfn1 protein, mouse; EC 3.6.1.-/Mfn2 protein, mouse; EC 3.6.5.-/Mfn1 protein, human
Comments/Corrections

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