Ki-S1 and Proliferating Cell Nuclear Antigen Expression of Bone Marrow Macrophages

The Journal of Immunology

Narayanan

Qian

et al. 2000

110

100

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.

Section: Discussionmentioning

confidence: 99%

Section: Nf-b As a Central Mediator In The Induction Of Tgf-␤ In Monomentioning

confidence: 99%

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

The Journal of Immunology

Narayanan

Qian

et al. 2000

110

100

“…28 One likely source is the macrophage, increased in MPD and activated in BM fibrosis. 6,17,48 Because macrophages express NK-1, 49-51 our findings might explain a potential mechanism for the activation of circulating monocytes reported for patients with myelofibrosis. 6,52 Interactions between circulating SP and NK-1 could induce cytokines.…”

Section: Discussionmentioning

confidence: 74%

Mimicry between neurokinin-1 and fibronectin may explain the transport and stability of increased substance P immunoreactivity in patients with bone marrow fibrosis

Joshi

Yadav

et al. 2001

Blood

Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases. In this study, the role of substance P (SP), a peptide with pleiotropic functions, was examined. Some of its functions-angiogenesis, fibroblast proliferation, and stimulation of BM progenitors-are amenable to inducing BM fibrosis. Indeed, a significant increase was found in SP-immunoreactivity (SP-IR) in the sera of patients with BM fibrosis (n ‫؍‬ 44) compared with the sera of patients with hematologic disorders and no histologic evidence of fibrosis (n ‫؍‬ 46) (140 ؎12 vs 18 ؎3; P < .01). Immunopre-

“…Monocytes and macrophages, which are increased in patients with BM fibrosis, have been suggested as candidate cells in the pathophysiology of BM fibrosis [7, 8, 55]. The prevalence of monocytes could be partly explained by the elevated levels of monocyte-differentiating factor, macrophage-colony-stimulating factor, in the circulation of patients with BM fibrosis [56].…”

Section: Relevant Potential Immune Andhematopoietic Cellsmentioning

confidence: 99%

“…Analyses of the NK-1 promoter [manuscript submitted] indicate that the expression of this gene in BM mesenchymal cells is regulated differently when compared to neural cells [72, 73]. Furthermore, since the NK-1 gene is induced by cytokines that are aberrantly regulated in patients with BM fibrosis [5, 7, 8, 51, 52, 53, 54, 55, 56], the molecular information on the regulation of NK-1 in a normal microenvironment might not be applicable to patients with BM fibrosis. If it is argued that the microenvironment of the brain and BM might influence the functions and regulation of the NK-1 receptor, then it could be assumed that the BM microenvironment of patients with myelofibrosis could be considered as a different tissue.…”

Section: Confounders and Potential Therapeutic Targetsmentioning

confidence: 99%

Substance P-Fibronectin-Cytokine Interactions in Myeloproliferative Disorders with Bone Marrow Fibrosis

Yook

et al. 2002

Acta Haematol

Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders: hematological and nonhematological. Clinical presentation of fibrosis could occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma. The pathophysiology underlying BM fibrosis remains unclear despite intensive study, with a corresponding lack of specific therapy. This review discusses new insights in the role of substance P, cytokines and fibronectin in the development of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic properties, e.g. neurotransmission and immune/hematopoietic modulation and is linked to BM fibrosis. Cytokines and growth factors, in particular those associated with fibrogenic properties, e.g. TGF-β, IL-1 and platelet-derived growth factor, are linked to BM fibrosis. Extracellular matrix proteins are increased in patients with BM fibrosis. Fibronectin in the sera of patients with BM fibrosis is complexed to substance P. Fibronectin appears to protect substance P from degradation by endogenous peptidases. This review describes the preliminary findings on the colocalization of substance P and fibronectin in the BM of patients with fibrosis. These data are reviewed in the context of published reports with particular focus on the relevant cytokines. A more detailed understanding of intra- and intercellular mechanisms in BM fibrosis may lead to effective therapy.