| pubmed-article:12521994 | pubmed:abstractText | Fanconi anemia complementation group C (Fancc)-deficient murine bone marrow progenitors demonstrate increased sensitivity to growth inhibition by interferon gamma (IFNgamma), tumor necrosis factor alpha (TNFalpha), and macrophage inflammatory protein 1alpha (MIP-1alpha). This property has been proposed as a possible pathogenic factor in the marrow failure seen in Fanconi anemia. Supporting our hypothesis that nitric oxide (NO) production might be a common effector in this sensitivity, we found that cytokine-mediated growth inhibition of Fancc(-/-) bone marrow cells was prevented by inhibiting NO synthase activity. Interestingly, Fancc(-/-) hematopoietic cells also exhibited increased growth inhibition on exposure to 2 distinct NO-generating agents, S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and diethylenetriamine nitric oxide adduct (DETA/NO). In keeping with the sensitivity of Fancc(-/-) cells to IFNgamma, inducible nitric oxide synthase (iNOS) levels and nitrite release were both increased following stimulation of Fancc(-/-) macrophages with this cytokine, either alone or in combination with bacterial lipopolysaccharide. Suggesting a plausible mechanism for the increased expression of iNOS, IFNgamma-stimulated Fancc(-/-) macrophages generated higher levels of phospho-Stat1, a positive regulator of inos (nos2) gene expression. These observations, while confined to C57BL/6 Fancc(-/-) hematopoietic cells, raise the possibility that nitric oxide has a role in the pathogenesis of Fanconi anemia. | lld:pubmed |
