Zinc and metallothioneins on cellular immune effectiveness during liver regeneration in young and old mice

Mocchegiani, Eugenio; Verbanac, Donatella; Santarelli, Lory; Tibaldi, Alberto; Muzzioli, Mario; Radošević-Stašić, Biserka; Milin, Čedomila

doi:10.1016/s0024-3205(97)00646-2

Cited by 33 publications

(22 citation statements)

References 47 publications

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“…Experimental zinc depletion and repletion of healthy humans revealed that secretion of the Th1-type cytokines IFN-gamma and IL 2 was decreased during zinc deficiency, whereas Th2-type cytokines (IL 4, IL 6, IL 10) were not affected (529). In animals, Mocchegiani et al (530) confirmed that oral zinc supplementation resulted in a recovery of thymic function (and also demonstrated its influence on extrathymic T cell differentiation pathways (531)) and showed that thymic regrowth was associated with a partial reconstitution of peripheral immune function (as measured by mitogen stimulated proliferation and NK activity). Moreover, low levels of activity of the zincdependent hormone thymulin were not dependent on the state of the thymus itself, but on decreased zinc saturation of the synthesized hormone.…”

Section: Vitamins and Minerals; Anti-oxidantsmentioning

confidence: 97%

T cells and aging (update February 1999)

Pawelec

1999

Front Biosci

113

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T cell immunosenescence 218effects of dysregulated immune responses in the elderly by supplementation or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age. FACTORS CONTRIBUTING TO IMMUNO-SENESCENCE HematopoiesisDysregulated hematopoiesis is seen in elderly individuals, raising the possibility that this could contribute to altered immune function in the aged. Hematopoiesis in man may be compromised because of a severely reduced capacity to produce colony stimulating factors (44) and increased production of pro-inflammatory factors such as IL 6 (45), because lower numbers of progenitor cells are present in the BM (46) and because of an age-related decline in proliferative potential of putative haematopoietic stem cells (HSC) (47). In mice, the repopulating potential of murine fetal liver-derived HSC is higher than that of adult BM-derived stem cells (48), suggesting possible aging of the HSC themselves. Normal cells with shorter telomeres possess less remaining replicative capacity than those with longer telomeres (see section 5.2). Accordingly, HSC from adult BM were found to have shorter telomeres than fetal liver-derived or umbilical cord-derived stem cells, consistent with aging of HSC (49). Telomere lengths decreased on culture despite low level expression of telomerase in these cells (50,51), although the rate of basepair loss per population doubling of cells in culture was lower during the first two weeks, when telomerase was upregulated, than in the next two, when it was downregulated (52). The telomerase expressed is therefore functionally active but may not be able to completely maintain telomere length in aging HSC cells. True embryonic stem cells (ESC), on the other hand, which may really be immortal, do retain high levels of telomerase activity (53). On the other hand, ESC from telomerase-knockout mice show gradual telomere shortening over many population doublings (PD) resulting in slowing and eventual cessation of growth (54). Certain animals which do not downregulate telomerase manifest a permanent growth phase and little or no senescence (55,56).

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Section: Vitamins and Minerals; Anti-oxidantsmentioning

confidence: 97%

T cells and aging (update February 1999)

Pawelec

1999

Front Biosci

113

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“…protective agent, on the other hand it may be dangerous for immune efficiency, as recently also suggested for increased metallothioneins in ageing: from protective in young age to dangerous role in old age for immune functions (Mocchegiani et al, 1997). Experimental evidence shows that zinc-bound active thymulin (ZnFTS) affects both in vivo (Bardos and Bach, 1982) and in vitro NK activity (Muzzioli et al, 1992), which is, in turn, under the control of IL-2 (Henney et al, 1981).…”

Section: Discussionmentioning

confidence: 97%

“…Intriguing points are also related to the role of zinc in the extrathymic T-cell pathway (Mocchegiani et al, 1997), which is important for NK-cell maturation in tumours (Seki et al, 1991). Thus, good zinc bioavailability may be crucial for the effectiveness of NK cells of thymic and extrathymic origin during cancer development.…”

Section: Discussionmentioning

confidence: 99%

Role of zinc and α2macroglobulin on thymic endocrine activity and on peripheral immune efficiency (natural killer activity and interleukin 2) in cervical carcinoma

et al. 1998

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Summary Decreased natural killer (NK) activity as well as interleukin 2 (IL-2) are risk factors for the progression of cervical carcinoma. NK activity and IL-2 may be thymus controlled. Plasma levels of active thymulin, a zinc-dependent thymic hormone (ZnFTS), are reduced in cancer because of the low peripheral zinc bioavailability. Zinc and thymulin are relevant for normal immune functions. α2-Macroglobulin is an inhibitor of matrix metalloproteases (MMPs) against invasive tumour proliferation. Because α 2 -macroglobulin has a binding affinity (K d ) for zinc that is higher than does thymulin, it may play a key role in immune efficiency in cancer. Plasma samples of 22 patients (age range 35-60 years) with locally advanced squamous cervical carcinoma and with FIGO stage Ib2-IIb were examined. They showed reduced active thymulin, decreased NK activity and IL-2 production, increased soluble IL-2 receptor (sIL-2R) and augmented α 2 -macroglobulin in the circulation, whereas plasma zinc levels were within the normal range for age. Significant positive correlations were found between zinc or active thymulin and α 2 -macroglobulin (r = 0.75, P < 0.01, r = 0.78, P < 0.01, respectively) in cancer patients. In vitro zinc increases IL-2 production from peripheral blood mononuclear cells (PBMCs) of cancer patients. These data suggest that an increase in α 2 -macroglobulin, which competes with thymulin for zinc binding, may be involved in causing a thymulin deficit with a consequent decrease of IL-2 and NK cytotoxicity. Thus, physiological zinc treatment in cervical carcinoma maybe restores impaired central and peripheral immune efficiency.

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“…Thus, the displacement of Zn by exogenous heavy metals is possible (190). Partial hepatectomy in young mice induces thymic atrophy and deregulation of thymocyte differentiation (192). This strongly suggests a link between the liver and the thymus in thymocyte development, and points to the contribution of zinc to this process.…”

Section: Non‐receptor‐mediated Effectsmentioning

confidence: 99%

Xenobiotic‐induced alterations in thymocyte development

Drela

2006

APMIS

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The thymus is a very sensitive target for environmental pollutants, which can affect this organ as well as thymocyte differentiation. A failure in thymocyte development can be due to the exacerbation of apoptosis, arrest of thymocyte maturation, generation of autoreactive T cells, and inhibition or stimulation of the output of recent thymic emigrants to the periphery. Recent data demonstrate that the immune system has the potential to maintain homeostasis under conditions of elevated risk, and the thymus plays a crucial role in this process. Environmental xenobiotics can exert their effects through receptor-mediated interactions or independently on receptor involvement. Under natural conditions organisms are exposed to a variety of xenobiotics. The final effect of such exposure is not related to the action of a single chemical, but to the action of a mixture of chemicals. The toxic effect of environmental xenobiotics on the generation and functions of immune cells may result in suppression or stimulation of the immune response. The most intensive studies have been done on halogenated aromatic hydrocarbons, heavy metals and various chemicals acting as endocrine disrupters. Recently, special interest has focused on the action of air particulate matter.

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Zinc and metallothioneins on cellular immune effectiveness during liver regeneration in young and old mice

Cited by 33 publications

References 47 publications

T cells and aging (update February 1999)

T cells and aging (update February 1999)

Role of zinc and α2macroglobulin on thymic endocrine activity and on peripheral immune efficiency (natural killer activity and interleukin 2) in cervical carcinoma

Xenobiotic‐induced alterations in thymocyte development

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