Differential induction of metallothionein synthesis by interleukin-6 and tumor necrosis factor-α in rat tissues

doi:10.1016/0192-0561(94)90075-2

International Journal of Immunopharmacology

Volume 16, Issue 2, February 1994, Pages 187-195

International Journa...

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Abstract

Metallothionein (MT) synthesis induced by the inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF), was studied in vivo. Administration of recombinant human IL-6 or TNF to rats caused the acute phase responses including rapid decreases in plasma zinc (Zn), and increases in plasma copper (Cu) and ceruloplasmin. Hepatic concentration of MT-I, one of MT isoforms, began to increase within 3 h after the injection of IL-6 or TNF. In IL-6-treated rats, MT-I concentration in liver reached a maximum level at 12 h and decreased with a transient rebound, whereas, in TNF-treated rats, a high level of MT-I lasted for about 48 h. MT-II, the other MT isoform, was induced more than MT-I in liver by both cytokines. MT-I was also induced in lung and heart by TNF, but little by IL-6. The data suggest that IL-6 may be responsible for MT synthesis in liver, whereas TNF may be responsible not only in liver but also in lung and heart. Furthermore plasma concentration of MT did not always reflect the enhanced concentration of MT by TNF and IL-6 in liver, suggesting involvement of many factors influencing plasma MT levels. The interrelation between IL-6 and TNF for MT synthesis has also been discussed.

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Citation Excerpt :
The upregulation of MT in the liver is mediated by a range of factors, including pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, tumour necrosis factor-ɑ (TNF-ɑ), interferon-gamma (IFN-ɣ), as well as stress hormones such as GC [36–38]. These factors are able to induce MT both independently and synergistically in different combinations in response to inflammatory stimuli resulting in different rates of MT biosynthesis at the site of inflammation [39–41]. The role of MT in Zn homeostasis under inflammatory conditions was initially reported in 1978 [42], and confirmed later [43–45].
Periodontitis (PD) is a multifaceted inflammatory disease connected to bacterial infection that results in the destruction of tooth supporting structures and eventually tooth loss. Given their involvement in infection and inflammation, both metallothionein (MT) and zinc (Zn) might play vital roles in the development and progression of PD. More specifically, both MT and Zn are heavily involved in regulating immune functions, controlling bacterial infection, balancing inflammatory responses, and reducing oxidative stress, all of which are associated with the pathogenesis of PD.
This review paper will explore the physiological functions of MT and Zn and hypothesise how dysregulation could negatively affect periodontal health, leading to PD.
Bacterial lipopolysaccharide (LPS) derived from periodontal pathogens, namely P. gingivalis initiates the acute phase response, thus upregulating the expression of MT which leads to the subsequent deficiency of Zn, a hallmark of periodontal disease. This deficiency leads to ineffective NETosis, increases the permeability of the gingival epithelium, and disrupts the humoral immune response, collectively contributing to PD. In addition, the presence of LPS in Zn deficient conditions favours M1 macrophage polarisation and maturation of dendritic cells, and also inhibits the anti-inflammatory activity of regulatory T cells. Collectively, these observations could theoretically give rise to the chronic inflammation seen in PD.
A disrupted MT and Zn homeostasis is expected to exert an adverse impact on periodontal health and contribute to the development and progression of PD.
Health and safety issues with plasticizers and plasticized materials: The influence of maternal nutrition on phthalate teratogenicity
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Involvement of the essential metal transporter Zip14 in hepatic Cd accumulation during inflammation
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Citation Excerpt :
These data suggest that hepatic uptake of Cd may be closely related to Zn metabolism. IL-6 has been shown to enhance the induction of hepatic MT synthesis in rat hepatocytes (Sato et al., 1994; Coyle et al., 1993). Hepatic MT concentration was significantly increased by LPS, Tur and Hex because all treatments caused an increase in plasma IL-6 levels and hepatic Zn concentration.
Upregulation of Zip14 contributes to hepatic zinc (Zn) and non-transferrin-bound iron (Fe) uptake during infection and inflammation. We investigated whether this essential metal transporter is also involved in hepatic cadmium (Cd) uptake under these conditions. An injection of lipopolysaccharide (LPS), turpentine oil (Tur) and n-hexane (Hex) resulted in an decrease in plasma Zn and Fe concentrations to 25–50% and an increase in hepatic concentrations of both metals to 150–200% of control mice. LPS significantly increased plasma interleukin (IL)-6 levels more rapidly than Tur or Hex. Tur or Hex significantly increased hepatic Zip14 mRNA expression and decreased ferroportin 1 mRNA expression following continuous increase of IL-6 level. Hepatic Cd and Zn concentrations increased significantly after repeated injections of Cd in Tur- or Hex-treated mice fed a control diet. Treatment with Tur or Hex additionally increased hepatic Cd accumulation in Zn-deficient mice, unlike in Fe-deficient mice. These results suggest that Zn transporters, such as Zip14, may be involved in hepatic Cd uptake during inflammation.
Tissue-dependent preventive effect of metallothionein against DNA damage in dyslipidemic mice under repeated stresses of fasting or restraint
2009, Life Sciences
To investigate the effect of repeated stress on DNA damage in seven organs of dyslipidemic mice, and the preventive role of metallothionein (MT).
Female adult 129/Sv wild-type and MT-null mice fed high-fat diet (HFD) were repeatedly subjected to mild stress of fasting or restraint in weeks 2 to 4 of 4-week study period. Serum cholesterol level, DNA damage in the liver, pancreas, spleen, bone marrow, kidney, lung and gastric mucosa, and other parameters were determined.
Body weights were increased in both types of mice fed HFD compared to those fed standard diet (STD), and further increased by 12 h-fasting, while they were markedly decreased by 1–3 h-restraint. Fasting accelerated accumulation of fat in the liver, and increase in serum cholesterol of both types of mice fed HFD. Feeding of HFD increased DNA damage in the pancreas, spleen and bone marrow of both types of mice, compared with those fed STD. In the wild-type mice fed HFD, 24 h-fasting increased DNA damage in the liver and spleen, while restraint increased the damage in the liver, pancreas, spleen and bone marrow. DNA damage in the cells of organs was markedly increased in the MT-null mice. Specifically, damage in the liver, pancreas, spleen and bone marrow was greatly increased with the intensity of stress increased, and the damage was much greater in the restraint mice than in the fasting mice.
MT plays a tissue-dependent preventive role against DNA damage in various murine organs induced by repeated stress.
Interferon alpha induction of metallothionein in rat liver is not linked to interleukin-1, interleukin-6, or tumor necrosis factor alpha
2005, Experimental and Molecular Pathology
Synthesis of metallothionein (MT) is induced by interferon-alpha (IFN-α) in vitro and in vivo. In addition, IFN-α promotes redistribution of zinc (Zn) from the plasma to the liver in mice. However, it is not clear if IFN-α induces hepatic MT synthesis directly or indirectly via liberation of other cytokines. In order to address this issue, we determined hepatic MT levels, Zn concentration in plasma, liver, and urine, and plasma levels interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα) in rats following intramuscular injection of human IFN-α (1.5 × 10⁶ UI/m²). Animals were housed in metabolic cages and sacrificed at various times after IFN-α administration. Zn concentrations in serum, urine, and hepatic tissue were determined by atomic absorption spectrophotometry. MT protein was measured using the MT silver saturation method and expression of MT-1 and MT-2 mRNA was measured by RT-PCR. Plasma levels of rat IL-1, IL-6, and TNFα were determined using an ELISA method. Hepatic MT levels began to increase at 2 h following IFN-α administration and reached maximum levels at 12 h post-treatment. Induction of MT gene expression was confirmed by increases in MT-1 and MT-2 mRNA levels 6, 12, and 18 h after IFN-α administration. IFN-α treatment also resulted in biphasic increases in hepatic Zn, with levels peaking at 2 h, the time-point when MT levels are first increased, and again at 18 h. Concurrently, there were decreases in serum Zn levels at these time points, suggesting IFN-α induced movement of Zn from the blood to hepatic tissue. The decrease in serum Zn was not due to increased excretion since urinary Zn levels were unaffected following IFN-α treatment. IFN-α administration had no effect on plasma IL-1, IL-6, and TNFα levels. These results show that IFN-α promotes the increase of hepatic MT levels and plasma/liver redistribution directly, without IL-1, IL-6, or TNFα participation.

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^☆: This work was presented in part at the 3rd International Meeting on Metallothionein, Tsukuba, Japan, 9 December 1992.

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International Journal of Immunopharmacology

Abstract

References (31)

Glucocorticoid independent mediation of interleukin-1 induced changes in serum zinc and liver metallothionein levels

Life Sci.

Endotoxin induction of hepatic metallothionein is mediated through cytokines

Toxic. appl. Pharmac.

Glucocorticoid inhibition of inflammation-induced metallothionien synthesis in mouse liver

Toxic. appl. Pharmac.

The induced synthesis of metallothionein in various tissues of rat in response to metals, I. Effect of repeated injection of cadmium salts

Toxicology

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J. Nutr.

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Chem. - Biol. Interac.

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Immun. Today

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Biochim. biophys. Acta

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Prog. Fd. Nutr. Sci.

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Interleukin-6 is the major regulator of acute phase protein synthesis in rat and man

Adv. Immunopharmac.

Tissue-specific regulation of zinc metabolism and metallothionein gene by interleukin 1

FASEB J.

Endotoxin induction of murine metallothionein gene expression

J. biol. Chem.

α-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences

Nature

Cited by (68)

HEALTH AND SAFETY ISSUES WITH PLASTICIZERS AND PLASTICIZED MATERIALS

Dysregulation of metallothionein and zinc aggravates periodontal diseases

Health and safety issues with plasticizers and plasticized materials: The influence of maternal nutrition on phthalate teratogenicity

Involvement of the essential metal transporter Zip14 in hepatic Cd accumulation during inflammation

Tissue-dependent preventive effect of metallothionein against DNA damage in dyslipidemic mice under repeated stresses of fasting or restraint

Interferon alpha induction of metallothionein in rat liver is not linked to interleukin-1, interleukin-6, or tumor necrosis factor alpha

Differential induction of metallothionein synthesis by interleukin-6 and tumor necrosis factor-α in rat tissues☆

Abstract

Life Sci.

Toxic. appl. Pharmac.

Toxic. appl. Pharmac.

Toxicology

J. Nutr.

Chem. - Biol. Interac.

Immun. Today

Biochim. biophys. Acta

Cachetin/tumor necrosis factor: production, distribution, and metabolic fate in vivo

J. Immun.

Interactions between metallothionein and trace metals

Prog. Fd. Nutr. Sci.

Radioimmunoassay of metallothionein in the assessment of the trace metal status of animals

Interleukin-6 is the major regulator of acute phase protein synthesis in rat and man

Adv. Immunopharmac.

Tissue-specific regulation of zinc metabolism and metallothionein gene by interleukin 1

FASEB J.

Endotoxin induction of murine metallothionein gene expression

J. biol. Chem.

α-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences

Nature