FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1? 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 ? (TNF-?), 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-?-resistant leukemic stem cell clones. In macrophages, the TNF-? overproduction phenotype depends on p38 mitogen-activated protein kinase (MAPK), an enzyme also known to induce expression of other inflammatory cytokines, including interleukin 1? (IL-1?). Reasoning that IL-1? 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-? and IL-1? in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1? potently suppressed the expansion of multipotent progenitor cells in vitro; and (3) although TNF-? overexpression in FA cells is controlled posttranscriptionally by the p38 substrate MAPKAPK-2, p38-dependent overproduction of IL-1? 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-1? or TNF-? alone.

SUBMITTER: Garbati MR 

PROVIDER: S-EPMC3814736 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature