Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine known to activate macrophages and T cells. In this study, we demonstrate that recombinant MIF delays apoptosis of neutrophils in vitro. MIF action is dose and time dependent as well as specific since it was abolished with a neutralizing anti-MIF antibody. MIF, like G-CSF, delayed cleavage of the proapoptotic members of the Bcl-2 family Bid and Bax in neutrophils, suggesting that MIF inhibits apoptosis pathways proximal to mitochondria activation. Indeed, MIF also prevented release of cytochrome c and Smac from the mitochondria and subsequent activation of the critical effector caspase-3 in these cells. Moreover, we observed increased MIF plasma levels in patients with cystic fibrosis, a heterogeneous recessive genetic disorder associated with bacterial infections and delayed neutrophil apoptosis. In conclusion, MIF is a survival cytokine for human neutrophils, a finding with potential pathologic relevance in infectious diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis* / drug effects
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BH3 Interacting Domain Death Agonist Protein
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Carrier Proteins / metabolism
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Caspase 3
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Caspases / metabolism
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Cells, Cultured
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Complement Membrane Attack Complex
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Complement System Proteins
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Cystic Fibrosis / immunology
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Cytochromes c / metabolism
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Glycoproteins / metabolism
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HeLa Cells
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Humans
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Kinetics
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Macrophage Migration-Inhibitory Factors / genetics
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Macrophage Migration-Inhibitory Factors / metabolism
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Macrophage Migration-Inhibitory Factors / pharmacology*
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Mitochondria / drug effects
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Mitochondria / metabolism*
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Neutrophils / drug effects
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Neutrophils / immunology*
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Neutrophils / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-bcl-2*
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RNA, Messenger / metabolism
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Signal Transduction
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bcl-2-Associated X Protein
Substances
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BAX protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Carrier Proteins
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Complement Membrane Attack Complex
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Glycoproteins
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Macrophage Migration-Inhibitory Factors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Messenger
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SC5b-9 protein complex
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bcl-2-Associated X Protein
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Complement System Proteins
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Cytochromes c
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CASP3 protein, human
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Caspase 3
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Caspases