| IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2-induced Bak interactions with mitofusins. | |
MedLine Citation:
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PMID: 19168699 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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:
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Aaron B Waxman; Narasaiah Kolliputi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-01-23 |
Journal Detail:
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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:
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Created Date: 2009-09-16 Completed Date: 2009-10-20 Revised Date: 2013-06-02 |
Medline Journal Info:
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Nlm Unique ID: 8917225 Medline TA: Am J Respir Cell Mol Biol Country: United States |
Other Details:
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Languages: eng Pagination: 385-96 Citation Subset: IM |
Affiliation:
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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. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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R01HL074859/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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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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