Submitted October 18, 2002
Accepted December 20, 2002
Increased sensitivity of Fancc-deficient hematopoietic cells to nitric oxide and evidence this species mediates growth inhibition by cytokines
Suzana Hadjur and Frank R Jirik*
Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
* Corresponding author; email: jirik{at}ucalgary.ca.
Fanconi anemia complementation group C (Fancc)-deficient murine bone marrow progenitors demonstrate increased sensitivity to growth inhibition by IFN
, TNF
, and MIP-1. 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 nitric oxide synthase activity. Interestingly, Fancc-/- hematopoietic cells also exhibited increased growth inhibition on exposure to two distinct NO-generating agents, SNAP and DETA/NO. In keeping with the sensitivity of Fancc-/- cells to IFN, 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, IFN-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 of nitric oxide having a role in the pathogenesis of Fanconi anemia.
