title: Role for the nuclear factor kappaB pathway in transforming growth factor-beta1 production in idiopathic myelofibrosis: possible relationship with FK506 binding protein 51 overexpression.
abstract: 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.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale U362, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805, Villejuif Cedex, France.
authors.forename: Emiko
authors.initials: E
authors.lastname: Komura
authors.forename: Carole
authors.initials: C
authors.lastname: Tonetti
authors.forename: Virginie
authors.initials: V
authors.lastname: Penard-Lacronique
authors.forename: Hédia
authors.initials: H
authors.lastname: Chagraoui
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacout
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Lecouédic
authors.forename: Philippe
authors.initials: P
authors.lastname: Rameau
authors.forename: Najet
authors.initials: N
authors.lastname: Debili
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
mesh_terms: 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
chemical_list: 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