title: TNF-alpha-dependent loss of IKKbeta-deficient myeloid progenitors triggers a cytokine loop culminating in granulocytosis.
abstract: 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 Ikkβ-deficient mice. TNF-α-dependent apoptosis of myeloid progenitor cells leads to the release of IL-1β, which promotes Th17 polarization of peripheral CD4(+) 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 Ikkβ-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.
authors.affiliation: Institute of Molecular Immunology, Klinikum Rechts der Isar, Technical University Munich, 81675 Munich, Germany.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Mankan
authors.forename: Ozge
authors.initials: O
authors.lastname: Canli
authors.forename: Sarah
authors.initials: S
authors.lastname: Schwitalla
authors.forename: Paul
authors.initials: P
authors.lastname: Ziegler
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004660:Encephalitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D023461:Myeloid Progenitor Cells / Q000276:immunology* / Q000378:metabolism; D038042:Myelopoiesis / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D053583:Interleukin-1beta; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse