Role of Heme–Hemopexin in Human T-Lymphocyte Proliferation

Smith, Ann; Eskew, Jeffrey D.; Borza, Corina M.; Pendrak, Michael L.; Hunt, Richard C.

doi:10.1006/excr.1997.3526

Cited by 30 publications

(23 citation statements)

References 36 publications

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“…For growth studies, cells seeded at an initial density of 2000 cells per well in 96-well plates were synchronized by incubation in DMEM containing 0.5% serum (LSDMEM) for 16 h before addition of increasing concentrations of sterilized (0.2-m nylon) heme-hemopexin. Cell number was assessed using the Promega Cell Titer proliferation assay as described previously for MOLT-3 cells (26). Initial experiments using direct cell counting confirmed the accuracy of this method under the experimental conditions investigated.…”

Section: Methodsmentioning

confidence: 86%

“…Heme-hemopexin targets heme to a discrete set of tissues and cells via selective expression of the hemopexin receptor and protects receptor null cells, including endothelial cells lining blood vessels, by preventing diffusion of free heme. Receptors for heme-hemopexin are expressed by liver parenchymal cells (25), lymphocytes (26), and cells of barrier tissues, e.g. retinal pigment epithelia (9) and probably also neurons of the peripheral (27) and central nervous systems (28).…”

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confidence: 99%

“…retinal pigment epithelia (9) and probably also neurons of the peripheral (27) and central nervous systems (28). Hemehemopexin has also recently been shown to act as a growth factor by providing a source of nutrient iron and activating PKC in human T-lymphocytes (26). As with other growth factors, the growth response curve is bell-shaped, raising the possibility that high levels of transported heme are deleterious to the cells or even toxic, although heme-hemopexin induces HO-1 and ferritin (9,15), and the heme-iron is rapidly incorporated into ferritin (29).…”

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confidence: 99%

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Cellular Protection Mechanisms against Extracellular Heme

Eskew

Vanacore

Sung

et al. 1999

Journal of Biological Chemistry

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Hemopexin protects cells lacking hemopexin receptors by tightly binding heme abrogating its deleterious effects and preventing nonspecific heme uptake, whereas cells with hemopexin receptors undergo a series of cellular events upon encountering heme-hemopexin. The biochemical responses to heme-hemopexin depend on its extracellular concentration and range from stimulation of cell growth at low levels to cell survival at otherwise toxic levels of heme. High (2-10 M) but not low (0.01-1 M) concentrations of hemehemopexin increase, albeit transiently, the protein carbonyl content of mouse hepatoma (Hepa) cells. This is due to events associated with heme transport since cobalt-protoporphyrin IX-hemopexin, which binds to the receptor and activates signaling pathways without tetrapyrrole transport, does not increase carbonyl content. WAF1/CIP1/SDI1 generated by heme-hemopexin appear to be of paramount importance in cellular protection by heme-hemopexin.

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Section: Methodsmentioning

confidence: 86%

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confidence: 99%

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confidence: 99%

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Cellular Protection Mechanisms against Extracellular Heme

Eskew

Vanacore

Sung

et al. 1999

Journal of Biological Chemistry

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“…In fact, the haptoglobin receptor, CD163, and hemopexin receptors have been implicated in cell survival, stress response, and inflammatory processes. [57][58][59][60][61] On the other hand, we and others previously observed that overexpression of HO-1 down-regulates adhesion molecule expression and subsequently reduces binding of leukocytes, whereas inhibition of HO activity exacerbates adhesion molecule expression and leukocyte infiltration mediated by proinflammatory mediators. 8,9,[26][27][28]62 This model of heme-HO-mediated modulation of inflammation is further strengthened by the findings of Willis and colleagues who demonstrated enhanced levels of HO-1 in monocytes during the resolution phase of inflammation.…”

Section: Discussionmentioning

confidence: 99%

The heme-heme oxygenase system: a molecular switch in wound healing

Wagener

Beurden

Hoff

et al. 2003

Blood

117

128

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When cells are injured they release their contents, resulting in a local accumulation of free heme proteins and heme. Here, we investigated the involvement of heme and its degrading enzyme heme oxygenase (HO) in the inflammatory process during wound healing. We observed that heme directly accumulates at the edges of the wound after inflicting a wound in the palate of Wistar rats. This coincided with an increased adhesion molecule expression and the recruitment of leukocytes. To prove that heme is responsible for the recruitment of leukocytes, heme was administered intradermally 24 hours prior to injury. A clear heme-induced influx of both macrophages and granulocytes was observed. When examining the HO isoforms, HO-1 and HO-2, we found that HO-2 was present in the entire submucosa. Surprisingly, we observed also that HO-1 is significantly expressed in the epithelium of both the mucosa and the skin of animals without wounds. On inflammation, HO-1 expression increased, particularly in infiltrating cells during the resolution phase of inflammation. Interestingly, we observed that heme-induced influx of leukocytes was highly elevated after pharmacologic inhibition of HO activity. These observations suggest that the heme-HO system is closely involved in the control of wound healing. Our results demonstrate that the local release of heme may be a physiologic trigger to start inflammatory processes, whereas HO-1 antagonizes inflammation by attenuating adhesive interactions and cellular infiltration. Moreover, the basal level of HO expression in the skin may serve as a first protective environment against acute oxidative and inflammatory insults. (Blood. 2003;102: 521-528)

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“…Lymphocytes may be able to use intracellularly stored Fe (Golding & Young, 1995). In addition, haem-haemopexin could substitute for Fe-transferrin in permitting proliferation of lymphoblastoid T-cells, with PKC activation again being implicated as a possible mechanism (Smith et al 1997). It is suggested that this mechanism of Fe uptake might be important at sites of injury or inflammation.…”

Section: Iron and Lymphocyte Functionmentioning

confidence: 99%