Role for the nuclear factor kappaB pathway in transforming growth factor-beta1 production in idiopathic myelofibrosis: possible relationship with FK506 binding protein 51 overexpression.
The release of transforming growth factor-beta1 (TGF-beta1) 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-beta1 synthesis is poorly known but seems regulated by nuclear factor kappaB (NF-kappaB). We previously described the overexpression of an immunophilin, FK506 binding protein 51 (FKBP51), in IMF megakaryocytes. Gel shift and gene assays show that FKBP51's overexpression in a factor-dependent hematopoietic cell line, induces a sustained NF-kappaB activation after cytokine deprivation. This activation correlates with a low level of IkappaBalpha. A spontaneous activation of NF-kappaB was also detected in proliferating megakaryocytes and in circulating CD34(+) patient cells. In normal cells, NF-kappaB activation was only detected after cytokine treatment. The expression of an NF-kappaB superrepressor in FKBP51 overexpressing cells and in derived megakaryocytes from CD34(+) of IMF patients revealed that NF-kappaB activation was not involved in the resistance to apoptosis after cytokine deprivation of these cells but in TGF-beta1 secretion. These results highlight the importance of NF-kappaB's 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.
Komura
Emiko
E
Institut National de la Sante et de la Recherche Medicale U362, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif Cedex, France.
Tonetti
Carole
C
Penard-Lacronique
Virginie
V
Chagraoui
Hédia
H
Lacout
Catherine
C
Lecouédic
Jean Pierre
JP
Rameau
Philippe
P
Debili
Najet
N
Vainchenker
William
W
Giraudier
Stéphane
S
D018952:Antigens, CD34 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055728:Primary Myelofibrosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D022021:Tacrolimus Binding Proteins / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D000099159:Tacrolimus Binding Protein 5
D018952:Antigens, CD34; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D022021:Tacrolimus Binding Proteins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000099159:Tacrolimus Binding Protein 5; C000606204:NFKBIA protein, human; C508960:TGFB1 protein, human