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

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