| First Author | Garbati MR | Year | 2013 |
| Journal | Blood | Volume | 122 |
| Issue | 18 | Pages | 3197-205 |
| PubMed ID | 24046015 | Mgi Jnum | J:204066 |
| Mgi Id | MGI:5529550 | Doi | 10.1182/blood-2013-02-484816 |
| Citation | Garbati MR, et al. (2013) FANCA and FANCC modulate TLR and p38 MAPK-dependent expression of IL-1beta in macrophages. Blood 122(18):3197-205 |
| abstractText | 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 bone marrow (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 1beta (IL-1beta). Reasoning that IL-1beta 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-1beta in a p38-dependent manner; (2) exposure of Fancc-deficient BM progenitors to IL-1beta 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-1beta 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-1beta or TNF-alpha alone. |
