Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acute Lung Injury / etiology
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Acute Lung Injury / physiopathology
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Acute Lung Injury / prevention & control
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Animals
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Apoptosis Regulatory Proteins / metabolism
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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GTP Phosphohydrolases / metabolism*
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Humans
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Hyperoxia / drug therapy*
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Hyperoxia / physiopathology
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Interleukin-6 / genetics
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Interleukin-6 / pharmacology
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Interleukin-6 / physiology*
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Lipid Peroxidation / drug effects
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Lung / drug effects*
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Lung / metabolism
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Lung / pathology
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Membrane Proteins / metabolism*
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Membrane Transport Proteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mitochondria / drug effects*
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Mitochondria / metabolism
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins / metabolism*
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Oxidative Stress / drug effects*
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Oxidative Stress / physiology
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Oxygen / toxicity*
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Protein Interaction Mapping
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / physiology*
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RNA, Small Interfering / pharmacology
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Recombinant Fusion Proteins / physiology
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bcl-2 Homologous Antagonist-Killer Protein / metabolism*
Substances
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Apoptosis Regulatory Proteins
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BAK1 protein, human
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Bak1 protein, mouse
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IL6 protein, human
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Interleukin-6
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Membrane Proteins
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Membrane Transport Proteins
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Mitochondrial Membrane Transport Proteins
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Mitochondrial Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Recombinant Fusion Proteins
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bcl-2 Homologous Antagonist-Killer Protein
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GTP Phosphohydrolases
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MFN2 protein, human
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Mfn1 protein, mouse
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Mfn2 protein, mouse
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Mfn1 protein, human
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Oxygen