Iron and Lymphocytes: Reciprocal Regulatory Interactions1

Sousa, Maria de; Reimão, R; Porto, Graça; Rw, Grady; Hilgartner, M W; Giardina, Patricia J.

doi:10.1159/000419357

Cited by 40 publications

(29 citation statements)

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“…[45][46][47][48] According to our data here, iron retention within the reticuloendothelial system observed in ACD may be due to: (1) increased acquisition of iron by monocytes due to the combined actions of pro-and anti-inflammatory cytokines on TfR-mediated and non-TfR-mediated iron uptake, and (2) down-regulation of ferroportin expression by IFN-␥ and LPS, leading to increased storage and retention of iron within monocytes. 3 As recent data indicate, DMT-1 also is localized to the late endosome in murine macrophages. 49 Since macrophages acquire iron also by phagocytosis of effete red blood cells, DMT-1 up-regulation and ferroportin depression under inflammatory conditions may contribute to an efficient recycling of hemoglobinderived iron and its retention within macrophages.…”

Section: Discussionmentioning

confidence: 88%

“…1,2 This is due, on the one hand, to divergent regulatory effects of the metal on immune cell proliferation 3 and on the effectiveness of cellular immune effector pathways. [4][5][6] On the other hand, cytokines derived from T cells and monocytes regulate cellular iron homeostasis by affecting the expression of proteins involved in the uptake and storage of the metal.…”

Section: Introductionmentioning

confidence: 99%

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Cytokine-mediated regulation of iron transport in human monocytic cells

Ludwiczek

Aigner

Theurl

et al. 2003

Blood

376

358

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Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)-dependent and -independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-␥ (IFN-␥) and lipopolysaccharide (LPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-␥ and LPS dosedependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-␥ and LPS downregulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-␥ and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention. IntroductionIron metabolism and immunity are closely interconnected. 1,2 This is due, on the one hand, to divergent regulatory effects of the metal on immune cell proliferation 3 and on the effectiveness of cellular immune effector pathways. [4][5][6] On the other hand, cytokines derived from T cells and monocytes regulate cellular iron homeostasis by affecting the expression of proteins involved in the uptake and storage of the metal. Proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), interleukin-1 (IL-1), or interleukin-6 (IL-6) directly stimulate the transcription and translation of the major iron storage protein ferritin, the latter by interfering with a so-called acute phase box. 7,8 Moreover, cytokines influence the posttranscriptional control of iron homeostasis by modulating the binding affinity of iron regulatory proteins (IRP-1 and IRP-2) to specific RNA stem loop structures, termed iron responsive elements (IREs), which are found within the 5Ј untranslated region of ferritin mRNA and within the 3Ј untranslated region of transferrin receptor (TfR) mRNA, the surface protein involved in the uptake of transferrinbound iron. Activation of IRP binding to IREs is controlled by intracellular iron availability, with IRP binding affinity being high when intracellular iron concentrations are low, thus resulting in stabilization of TfR mRNA while ferritin translation is reduced (fo...

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Cytokine-mediated regulation of iron transport in human monocytic cells

Ludwiczek

Aigner

Theurl

et al. 2003

Blood

376

358

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“…These results include data demonstrating that (i) recombinant HFE reduces the affinity of the TfR for holotransferrin, (ii) HFE can compete with Tf for binding to TfR, and (iii) HFE reduces the endocytosis rate of HFE/TfR/Tf complexes. However, these data do not preclude the possibility that HFE complexed with other proteins may affect, directly or indirectly, other types of iron transport systems or immune responses (6,8,25,26,30,36). By virtue of being a class I MHC molecule, HFE complexes might be modulated by viral antigens and might thus manifest another target for virus manipulation of cellular proteins.…”

mentioning

confidence: 95%

Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

Ben-Arieh

Zimerman

Smorodinsky

et al. 2001

J Virol

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HFE is a nonclassical class I major histocompatibility complex (MHC) molecule that is mutated in the autosomal recessive iron overload disease hereditary hemochromatosis. There is evidence linking HFE with reduced iron uptake by the transferrin receptor (TfR). Using a panel of HFE and TfR monoclonal antibodies to examine human HFE (hHFE)-expressing cell lines, we demonstrate the expression of stable and fully glycosylated TfR-free and TfR-associated hHFE/␤2m complexes. We show that both the stability and assembly of hHFE complexes can be modified by the human cytomegalovirus (HCMV) viral protein US2, known to interfere with the expression of classical class I MHC molecules. HCMV US2, but not US11, targets HFE molecules for degradation by the proteasome. Whether this interference with the regulation of iron metabolism by a viral protein is a means of potentiating viral replication remains to be determined. The reduced expression of classical class I MHC and HFE complexes provides the virus with an efficient tool for altering cellular metabolism and escaping certain immune responses.

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“…This is consistent with retained IL-4 production and intact humoral antibody-mediated immunity. More pertinently to the bacterial pathogens discussed in this article, iron overload appears to potently impair the macrophage and neutrophil arms of the innate immune response from antibody-mediated and opsonin-dependent phagocytosis (19,36,44). For example, one study demonstrated that a hemochromatosis patient with Listeria meningitis showed a diminished capacity to phagocytose S. aureus, a phenomenon which was reversible by repeated ironreducing phlebotomies.…”

Section: Iron and The Host Immune Systemmentioning

confidence: 99%

Hepcidin: the Missing Link between Hemochromatosis andInfections

Ashrafian

2003

Infect Immun

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The aphrodisiacal potential of oysters is the stuff of maritime folklore, having roots in tales of Aphrodite (literally "foam born"), the goddess of love, said to have arisen from the sea on an oyster shell. However, mariners' tales chronicling oysters' lethal potential, despite having abounded since the 5th century B.C., have received less attention. Vibrio vulnificus, originally described in 1979 (6; J. J. Farmer III, Letter, Lancet ii:903, 1979), is a particularly virulent, lactose-fermenting, motile gram-negative halophilic bacterium that inhabits temperate coastal waters, notably of the Gulf of Mexico. V. vulnificus is concentrated in fish and filter feeders such as oysters and clams (up to 50% culture positive) and crabs (up to 11% culture positive) (18,72), and infection associated with exposure to this organism may range from wound infections to fatal septicemic shock (38, 69). Moreover, as probably the leading cause of seafood-associated fatalities in the United States, this organism is considered a significant public health hazard, since despite early recognition, aggressive antibiotic therapy, and surgical debridement, the morbidity, mortality, and cost associated with V. vulnificus infections remain substantial (48,49).Risk factors for V. vulnificus infection include the V. vulnificus subtype (various genetically distinct subgroups of biotype 1 identified by randomly amplified polymorphic DNA PCR appear to be especially virulent), immunocompromised state (human immunodeficiency virus, cancer, bone marrow suppression, achlorhydria, and diabetes), end-stage renal impairment, liver impairment (particularly cirrhosis [infection risk, 200-fold]) (33), and hemochromatosis (primary or secondary such as the hemolytic anemias and thalassemias or porphyria cutanea tarda) (11,30,31,51,71). Interestingly, these same patients, especially those with iron overload, also have a striking predisposition to other aggressive bacteria, including Listeria monocytogenes, Klebsiella sp., and Yersinia sp. (the last of these, perhaps coincidentally, is also a potentially waterborne

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Iron and Lymphocytes: Reciprocal Regulatory Interactions1

Cited by 40 publications

References 0 publications

Cytokine-mediated regulation of iron transport in human monocytic cells

Cytokine-mediated regulation of iron transport in human monocytic cells

Human Cytomegalovirus Protein US2 Interferes with the Expression of Human HFE, a Nonclassical Class I Major Histocompatibility Complex Molecule That Regulates Iron Homeostasis

Hepcidin: the Missing Link between Hemochromatosis andInfections

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