Role for the nuclear factor κB pathway in transforming growth factor-β1 production in idiopathic myelofibrosis:: Possible relationship with FK506 binding protein 51 overexpression

The release of transforming growth factor-beta 1 (TGF-beta 1) in the bone marrow microenvironment is one of the main mechanisms leading to myelofibrosis in murine models and probably in the human idiopathic myelofibrosis (IMF). The regulation of TGF-beta 1 synthesis is poorly known but seems regulated by nuclear factor kappa B (NF-kappa B). We previously described the overexpression of an immunophilin, FK506 binding protein 51 (FKBP51), in IMF megakaryocytes. Gel shift and gene assays show that FKBP51s overexpression in a factor-dependent hematopoietic cell line, induces a sustained NF-kappa B activation after cytokine deprivation. This activation correlates with a low level of I kappa B alpha. A spontaneous activation of NF-kappa B was also detected in proliferating megakaryocytes and in circulating CD34(+) patient cells. In normal cells, NF-kappa B activation was only detected after cytokine treatment. The expression of an NF-kappa B superrepressor in FKBP51 over-expressing cells and in derived megakaryocytes from CD34+ of IMF patients revealed that NF-kappa B activation was not involved in the resistance to apoptosis after cytokine deprivation of these cells but in TGF-beta 1 secretion. These results highlight the importance of NF-kappa Bs activation in the fibrosis development of this disease. They also suggest that FKBP51's overexpression in IMF cells could play an important role in the pathogenesis of this myeloproliferative disorder.