NF-κB as a Central Mediator in the Induction of TGF-β in Monocytes from Patients with Idiopathic Myelofibrosis: An Inflammatory Response Beyond the Realm of Homeostasis

Abstract

Immune-mediated mechanisms have been implicated in the etiology of idiopathic bone marrow fibrosis (IMF). However, the mechanism remains poorly defined. Compared with healthy controls, IMF monocytes are overactivated, with increased production of TGF-β and IL-1. TGF-β is central to the progression of fibrosis in different organs. In the lung, fibrosis is associated with up-regulation of TGF-β-inducible genes. Because IL-1 and TGF-β have pro- and antiinflammatory properties and neither appears to regulate the high levels of each other in IMF, we studied the mechanism of this paradigm. We focused on the role of RelA, a subunit of the transcription factor, NF-κB that is associated with inflammatory responses. We transiently knocked out RelA from IMF monocytes with antisense oligonucleotides and showed that RelA is central to IL-1 and TGF-β production and to the adhesion of IMF monocytes. Because the NF-κB family comprises subunits other than RelA, we used aspirin and sodium salicylate to inhibit kinases that activate NF-κB and showed effects similar to those of the RelA knockout system. It is unlikely that RelA could be interacting directly with the TGF-β gene. Therefore, we determined its role in TGF-β production and showed that exogenous IL-1 could induce TGF-β and adherence of IMF monocytes despite the depletion of NF-κB. The results indicate that IL-1 is necessary for TGF-β production in IMF monocytes, but NF-κB activation is required for the production of endogenous IL-1. Initial adhesion activates NF-κB, which led to IL-1 production. Through autocrine means, IL-1 induces TGF-β production. In total, these reactions maintain overactivation of IMF monocytes.

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

“…Endothelin-1 transcription is controlled by NF-B in vascular endothelium (54), and endothelin-1 itself is proinflammatory, because it activates NF-B in macrophages (55). Interstitial fibrosis caused by CsA is associated with increased expression of TGF-␤1 (56), and TGF-␤1 is responsive to induction by IL-1 in macrophages, which activates NF-B and several other transcription factors (57). IL-6 has been reported to contribute to nephrotoxicity (58,59), and FK506 induces IL-6 production in fibroblasts through the activation of NF-B (60).…”

Overexpression of FKBP51 in idiopathic myelofibrosis regulates the growth factor independence of megakaryocyte progenitors

“…However, another hypothesis was proposed that placed monocytes as a central key in the pathogenesis of fibrosis. 8,15 Therefore, it is not excluded that the combination of an MK hyperplasia and a monocyte activation is required to obtain the development of a myelofibrosis. Whatever the precise mechanism, MK hyperplasia is a key phenomenon in the development of IMF.…”

“…However, monocytes/ macrophages may also play an important role in this disease. A spontaneous activation of the nuclear factor-B (NF-B) pathway has been described in patient monocytes 15 ; second, although TPO induced a myelofibrosis in severe combined immunodeficient (SCID) mice, no myelofibrosis could be observed in nonobese diabetic-SCID (NOD-SCID) mice. 8 Because NOD-SCID mice have also a monocyte defect, this result suggests that monocytes in combination with MKs are required to induce a myelofibrosis.…”

Targeting NF-κB in hematologic malignancies

“…79 Recently, it has been reported that monocytes from IMF patients presented constitutive activation of NF-kB associated with TGF-b1 secretion. 80 Another study demonstrated the spontaneous activity of the NF-kB pathway in IMF CD34 þ cells and megakaryocytes and the NF-jB in hematologic malignancies T Braun et al implication of the immunophilin FK506-binding protein 51 (FKBP51), probably leading to activation of NF-kB composed by p65/p50 subunits. 79 Inhibition of NF-kB activity by the NFkB super-repressor did not alter resistance to apoptosis, but inhibited secretion of TGF-b1.…”