FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages

Michael R. Garbati, Laura E. Hays, Winifred Keeble, Jane E. Yates, R. Keaney Rathbun, Grover C. Bagby

    Research output: Contribution to journalArticle

    19 Scopus citations


    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-a-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.

    Original languageEnglish (US)
    Pages (from-to)3197-3205
    Number of pages9
    Issue number18
    StatePublished - 2013

    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

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    Garbati, M. R., Hays, L. E., Keeble, W., Yates, J. E., Rathbun, R. K., & Bagby, G. C. (2013). FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1β in macrophages. Blood, 122(18), 3197-3205.