Abstract
Hematopoietic stem and progenitor cells with inactivated Fanconi anemia (FA) genes, FANCA and FANCC, are hypersensitive to inflammatory cytokines. One of these, tumor necrosis factor α (TNF-α), is also overproduced by FA mononuclear phagocytes in response to certain Toll-like receptor (TLR) agonists, creating an autoinhibitory loop that may contribute to the pathogenesis of progressive bone marrow (BM) failure and selection of TNF-α-resistant leukemic stem cell clones. In macrophages, the TNF-α overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1β (IL-1β). Reasoning that IL-1β might be involved in a like autoinhibitory loop, we determined that (1) TLR activation of FANCA- and FANCC-deficient macrophages induced overproduction of both TNF-α and IL-1β in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1β potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-α overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1β is controlled transcriptionally. We suggest that multiple inflammatory cytokines overproduced by FANCA- and FANCC-deficient mononuclear phagocytes may contribute to the progressive BM failure that characterizes FA, and that to achieve suppression of this proinflammatory state, p38 is a more promising molecular therapeutic target than either IL-1β or TNF-α alone.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cells, Cultured
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Fanconi Anemia Complementation Group A Protein / genetics
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Fanconi Anemia Complementation Group A Protein / metabolism*
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Fanconi Anemia Complementation Group C Protein / genetics
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Fanconi Anemia Complementation Group C Protein / metabolism*
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / metabolism
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Humans
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Imidazoles / pharmacology
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Inflammasomes / genetics
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Inflammasomes / metabolism
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism*
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Interleukin-1beta / pharmacology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism*
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Mice, Knockout
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Naphthalenes / pharmacology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Pyrazoles / pharmacology
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Toll-Like Receptors / agonists
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Toll-Like Receptors / metabolism*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Fanconi Anemia Complementation Group A Protein
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Fanconi Anemia Complementation Group C Protein
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Imidazoles
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Inflammasomes
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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Naphthalenes
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Pyrazoles
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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MAP-kinase-activated kinase 2
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Protein Serine-Threonine Kinases
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p38 Mitogen-Activated Protein Kinases
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doramapimod
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resiquimod