TNF-α–dependent loss of IKKβ-deficient myeloid progenitors triggers a cytokine loop culminating in granulocytosis
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- Arun K. Mankan
- Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany;
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- Ozge Canli
- Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany;
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- Sarah Schwitalla
- Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany;
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- Paul Ziegler
- Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany;
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- Jurg Tschopp
- Department of Biochemistry, Center of Immunity and Infection, University of Lausanne, CH-1066 Epalinges, Switzerland; and
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- Thomas Korn
- Department of Neurology, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany
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- Florian R. Greten
- Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany;
説明
<jats:p> Loss of IκB kinase (IKK) β-dependent NF-κB signaling in hematopoietic cells is associated with increased granulopoiesis. Here we identify a regulatory cytokine loop that causes neutrophilia in <jats:italic>Ikkβ</jats:italic> −deficient mice. TNF-α–dependent apoptosis of myeloid progenitor cells leads to the release of IL-1β, which promotes Th17 polarization of peripheral CD4 <jats:sup>+</jats:sup> T cells. Although the elevation of IL-17 and the consecutive induction of granulocyte colony-stimulating factor compensate for the loss of myeloid progenitor cells, the facilitated induction of Th17 cells renders <jats:italic>Ikkβ</jats:italic> -deficient animals more susceptible to the development of experimental autoimmune encephalitis. These results unravel so far unanticipated direct and indirect functions for IKKβ in myeloid progenitor survival and maintenance of innate and Th17 immunity and raise concerns about long-term IKKβ inhibition in IL-17–mediated diseases. </jats:p>
収録刊行物
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- Proceedings of the National Academy of Sciences
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Proceedings of the National Academy of Sciences 108 (16), 6567-6572, 2011-04-04
Proceedings of the National Academy of Sciences
