Abstract
This article shows that T cell activation-induced expression of the cytokines IL-2 and -4 is determined by an oxidative signal originating from mitochondrial respiratory complex I. We also report that ciprofloxacin, a fluoroquinolone antibiotic, exerts immunosuppressive effects on human T cells suppressing this novel mechanism. Sustained treatment of preactivated primary human T cells with ciprofloxacin results in a dose-dependent inhibition of TCR-induced generation of reactive oxygen species (ROS) and IL-2 and -4 expression. This is accompanied by the loss of mitochondrial DNA and a resulting decrease in activity of the complex I. Consequently, using a complex I inhibitor or small interfering RNA-mediated downregulation of the complex I chaperone NDUFAF1, we demonstrate that TCR-triggered ROS generation by complex I is indispensable for activation-induced IL-2 and -4 expression and secretion in resting and preactivated human T cells. This oxidative signal (H(2)O(2)) synergizes with Ca(2+) influx for IL-2/IL-4 expression and facilitates induction of the transcription factors NF-kappaB and AP-1. Moreover, using T cells isolated from patients with atopic dermatitis, we show that inhibition of complex I-mediated ROS generation blocks disease-associated spontaneous hyperexpression and TCR-induced expression of IL-4. Prolonged ciprofloxacin treatment of T cells from patients with atopic dermatitis also blocks activation-induced expression and secretion of IL-4. Thus, our work shows that the activation phenotype of T cells is controlled by a mitochondrial complex I-originated oxidative signal.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cells, Cultured
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Ciprofloxacin / pharmacology*
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DNA, Mitochondrial / antagonists & inhibitors
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DNA, Mitochondrial / genetics
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Dermatitis, Atopic / enzymology
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Dermatitis, Atopic / genetics
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Dermatitis, Atopic / immunology
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Electron Transport Complex I / antagonists & inhibitors
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Electron Transport Complex I / deficiency
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Electron Transport Complex I / genetics
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / immunology
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Humans
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Immunophenotyping
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Immunosuppressive Agents / pharmacology*
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Interleukin-2 / antagonists & inhibitors
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Interleukin-2 / genetics*
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Interleukin-2 / metabolism
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Interleukin-4 / antagonists & inhibitors
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Interleukin-4 / genetics*
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Interleukin-4 / metabolism
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Jurkat Cells
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Mitochondria / drug effects
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Mitochondria / enzymology
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Mitochondria / metabolism*
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NADH Dehydrogenase / antagonists & inhibitors
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NADH Dehydrogenase / genetics
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RNA, Small Interfering / pharmacology
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Reactive Oxygen Species / antagonists & inhibitors
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Reactive Oxygen Species / metabolism*
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Receptors, Antigen, T-Cell / antagonists & inhibitors
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Receptors, Antigen, T-Cell / biosynthesis
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Receptors, Antigen, T-Cell / genetics
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T-Lymphocytes / drug effects
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T-Lymphocytes / enzymology
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T-Lymphocytes / immunology*
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Th2 Cells / drug effects
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Th2 Cells / enzymology
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Th2 Cells / immunology
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Time Factors
Substances
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DNA, Mitochondrial
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IL2 protein, human
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IL4 protein, human
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Immunosuppressive Agents
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Interleukin-2
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RNA, Small Interfering
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Reactive Oxygen Species
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Receptors, Antigen, T-Cell
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Interleukin-4
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Ciprofloxacin
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NADH Dehydrogenase
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Electron Transport Complex I
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NDUFAF1 protein, human