title: FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages.
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.
authors.affiliation: Oregon Health & Science University, Portland, OR;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Garbati
authors.forename: Laura E
authors.initials: LE
authors.lastname: Hays
authors.forename: Winifred
authors.initials: W
authors.lastname: Keeble
authors.forename: Jane E
authors.initials: JE
authors.lastname: Yates
authors.forename: R Keaney
authors.initials: RK
authors.lastname: Rathbun
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics / Q000378:metabolism*; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D009281:Naphthalenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2; D010671:Phenylurea Compounds
chemical_list: D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; D007093:Imidazoles; D058847:Inflammasomes; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D009281:Naphthalenes; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C452139:doramapimod; D010671:Phenylurea Compounds; C402365:resiquimod
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