Cachectin/tumor necrosis factor‐α alters red blood cell kinetics and induces anemia in vivo

Moldawer, Lyle L.; Marano, Michael A.; He, Wei; Fong, Yuman; Silen, Mark L.; Kuo, George; Manogue, Kirk R.; Vlassara, Helen; Cohen, Harvey J.; Cerami, Anthony

doi:10.1096/fasebj.3.5.2784116

Cited by 209 publications

(109 citation statements)

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Section: Introductionmentioning

confidence: 93%

“…However, inflammation may increase the uptake of other forms of iron. Enhanced divalent metal transporter1-mediated acquisition of non-transferrin-bound iron has been described in cytokine-stimulated human monocytic cell lines [19] and the increased erythrophagocytosis reported in TNF-a-stimulated macrophages could increase the acquisition of heme iron [21].Most of the information available concerning the molecular regulation of macrophage iron metabolism during inflammation has come from studies in which macrophage cell lines or freshly isolated monocytes/macrophages have been challenged with LPS/IFN-g, a model system that mimicks exposure to micro-organisms and/or Th1 pro-inflammatory cytokines (see [6] for a recent review). However, cells of the monocyte-macrophage lineage are characterized by marked phenotypical and functional heterogeneity [22][23][24].…”

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confidence: 94%

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Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions, mimicked by the combined action of LPS and IFN-c (M1 polarization). However, macrophages can undergo an alternative type of activation stimulated by Th2 cytokines, and acquire a role in cell growth and tissue repair control (M2 polarization). We characterized the expression of genes related to iron homeostasis in fully differentiated unpolarized (M0), M1 and M2 human macrophages. The molecular signature of the M1 macrophages showed changes in gene expression (ferroportin repression and H ferritin induction) that favour iron sequestration in the reticuloendothelial system, a hallmark of inflammatory disorders, whereas the M2 macrophages had an expression profile (ferroportin upregulation and the downregulation of H ferritin and heme oxygenase) that enhanced iron release. The conditioned media from M2 macrophages promoted cell proliferation more efficiently than those of M1 cells and the effect was blunted by iron chelation. The role of ferroportin-mediated iron release was demonstrated by the absence of differences from the media of macrophages of a patient with loss of function ferroportin mutation. The distinct regulation of iron homeostasis in M2 macrophages provides insights into their role under pathophysiological conditions. Key words: Immune system . Iron . Polarized macrophages IntroductionMacrophages play a critical role in body iron homeostasis by recovering iron from old red blood cells and returning it to the circulation for binding to transferrin, which delivers the metal to the cells that need it for various functions, thus contributing more than 80% to daily iron turnover [1][2][3].Iron retention in the reticuloendothelial system is the main response of body iron homeostasis to inflammation and is regarded as a host's attempt to withhold iron from the invading pathogens [4]. This restricts iron availability for erythroid progenitor cells and may contribute toward causing the common condition of inflammation-related anaemia [1,5,6]. Increased iron retention within inflammatory macrophages is due to increased iron uptake and decreased iron export [7], and is favoured by the induction of the iron storage protein ferritin (Ft) [8,9]. The blockade of macrophage iron release is mainly due to the interaction between the acute phase protein hepcidin and the iron exporter ferroportin (Fpn) [1][2][3], as the increase in circulating hepcidin triggered by inflammatory cytokines causes the internalization and degradation of Fpn [10], the exporter of non-heme iron [11], thus blocking iron release from macrophages.Macrophage Fpn is also negatively regulated at transcriptional and post-transcriptional levels by inflammatory mediators [12][13][14]. It is still unknown whether the inflammatory response affects the feline leukemia virus, subgroup C, receptor that exports heme from macrophages [15] and whether the heme transporter HRG1 proteins play a role in macrophage iron metabolism [16]. O...

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Section: Introductionmentioning

confidence: 93%

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confidence: 94%

Differential regulation of iron homeostasis during human macrophage polarized activation

et al. 2010

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“…In initial studies carried out in vivo 64,65 and in vitro, 66 evidence was provided that TNF-a exerted an inhibitory effect on erythropoiesis. In addition, in a phase I study of TNF-a in cancer patients, a clear decrease in hemoglobin levels after 1 month of TNF-a treatment was observed.…”

Section: Role Of Cell Death Receptors In the Control Of Erythropoiesismentioning

confidence: 99%

Apoptotic mechanisms in the control of erythropoiesis

2004

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Erythropoiesis is a complex multistep process encompassing the differentiation of hemopoietic stem cells to mature erythrocytes. The steps involved in this complex differentiation process are numerous and involve first the differentiation to early erythoid progenitors (burst-forming units-erythroid, BFU-E), then to late erythroid progenitors (colony-forming unitserythroid) and finally to morphologically recognizable erythroid precursors. A key event of late stages of erythropoiesis is nuclear condensation, followed by extrusion of the nucleus to produce enucleated reticulocytes and finally mature erythrocytes. During the differentiation process, the cells became progressively sensitive to erythropoietin that controls both the survival and proliferation of erythroid cells.A normal homeostasis of the erythropoietic system requires an appropriate balance between the rate of erythroid cell production and red blood cell destruction. Growing evidences outlined in the present review indicate that apoptotic mechanism play a relevant role in the control of erythropoiesis under physiologic and pathologic conditions. Withdrawal of erythropoietin or stimulation of death receptors such as Fas or TRAIL-Rs leads to activation of a subset of caspases-3, -7 and -8, which then cleave the transcription factors GATA-1 and TAL-1 and trigger apoptosis. In addition, there is evidence that a number of caspases are physiologically activated during erythroid differentiation and are functionally required for erythroid maturation. Several caspase substrates are cleaved in differentiating cells, including the protein acinus whose activation by cleavage is required for chromatin condensation.The studies on normal erythropoiesis have clearly indicated that immature erythroid precursors are sensitive to apoptotic triggering mediated by activation of the intrinsic and extrinsic apoptotic pathways. These apoptotic mechanisms are frequently exacerbated in some pathologic conditions, associated with the development of anemia (ie, thalassemias, multiple myeloma, myelodysplasia, aplastic anemia).The considerable progress in our understanding of the apoptotic mechanisms underlying normal and pathologic erythropoiesis may offer the way to improve the treatment of several pathologic conditions associated with the development of anemia.

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“…27 This stimulation may be direct activation of the TNF-␣ receptor or secondary effects resulting from TNF-␣-dependent secretion of an intermediate factor such as granulocyte-macrophage colonystimulating factor. 28 TNF-␣ has been shown to inhibit erythropoiesis, [29][30][31] although it has been demonstrated that the inhibitory effects of TNF-␣ were likely mediated by ␤-interferon produced by macrophages in response to TNF-␣ and not due to direct actions of TNF-␣. 32,33 TNF-␣ also has been reported to promote proliferation of CD34 ϩ human hematopoietic cells.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia

Jacobs-Helber

Roh

Bailey

et al. 2003

Blood

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Cachectin/tumor necrosis factor‐α alters red blood cell kinetics and induces anemia in vivo

Cited by 209 publications

References 1 publication

Differential regulation of iron homeostasis during human macrophage polarized activation

Differential regulation of iron homeostasis during human macrophage polarized activation

Apoptotic mechanisms in the control of erythropoiesis

Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia

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