Hepatic Metallothionein Induction in Inflammation*†

Sobocinski, P Z; Canterbury, W J

doi:10.1111/j.1749-6632.1982.tb22149.x

Cited by 54 publications

(14 citation statements)

References 28 publications

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“…It has been proposed that LPS induces the uptake of Zn by the liver (20). We therefore measured the amount of Zn accumulated by the tissues during the 9-hr time course to discern whether LPS could be inducing MT-I mRNA accumulation by a Zn-mediated process.…”

Section: Resultsmentioning

confidence: 99%

“…It has been previously shown that serum Zn levels are decreased by a variety of stresses, including LPS injection (20,21). Sobocinski et al (20) suggested that this drop in serum Zn results from an uptake of Zn by the liver, which in turn results in the induction of hepatic MT.…”

Section: Discussionmentioning

confidence: 99%

“…Sobocinski et al (20) suggested that this drop in serum Zn results from an uptake of Zn by the liver, which in turn results in the induction of hepatic MT. Our data do not support this hypothesis because we measured no change in either renal or hepatic Zn levels during the early phase of MT-I mRNA induction by LPS.…”

Section: Discussionmentioning

confidence: 99%

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Induction of mouse metallothionein-I mRNA by bacterial endotoxin is independent of metals and glucocorticoid hormones.

Durnam¹,

Hoffman²,

Quaife³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

132

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Induction of metallothionein-I (MT-I) mRNA by bacterial endotoxin (LPS) was examined. A single injection of LPS induced MT-I mRNA accumulation in both liver and kidney comparable to that induced by heavy metals. Maximal message levels were achieved 6 hr after LPS administration, prior to any increase in either hepatic or renal Zn or Cu. Experiments in which LPS was administered to transgenic mice harboring recombinant genes made by fusing the MT-I gene promoter to the herpes simplex virus thymidine kinase structural gene revealed that the response to LPS is independent of glucocorticoid hormones. These experiments begin to define the region of the MT-I gene promoter required for the LPS response.It has been well documented that the synthesis of metallothionein (MT) is regulated by both heavy metals, such as Cd and Zn, and glucocorticoid hormones (1-4). We have shown both in vivo and in cultured cells that the regulation of the mouse MT-I gene occurs primarily at the level of gene transcription for both classes of inducers (5-7). Definition of the region(s) of the MT-I gene promoter necessary for regulation by heavy metals has been approached by fusing deleted variants of the MT-I gene promoter to easily assayable genes, such as the herpes simplex virus (HSV) thymidine kinase (TK) gene, and analyzing metal regulation after the fused genes were introduced into either tissue culture cells or mouse eggs (8,9). These studies indicate that the region of the mouse MT-I promoter necessary for metal regulation maps within 90 nucleotides 5' of the normal MT-I transcription initiation site. Similar analysis of the region important for glucocorticoid regulation has not been possible because the mouse MT-I promoter is not responsive to glucocorticoids when transferred to other cells (9-11).In Like MT, some acute-phase proteins are regulated by elevated glucocorticoid levels resulting from stresses such as surgical trauma, pain, apprehension, and exposure to heat and cold (14-17). However, for MTs the response to inflammatory agents does not appear to be glucocorticoid-mediated because it has been recently shown that the injection of turpentine induced comparable amounts of hepatic MT in adrenalectomized and control rats (18). This suggests that there may be several mechanisms regulating MT synthesis that are operative during different types of stress and implies that perhaps a third class of regulatory molecule can affect MT-I gene transcription. Here we present several lines of evidence that rule out metal or glucocorticoid involvement in the response to the potent inflammatory agent LPS and thus support the notion that a third class of molecules may mediate MT-I gene expression during stress. MATERIALS AND METHODSMT-I mRNA Accumulation Time Course. Male SwissWebster mice, 14-17 g, were injected subcutaneously with ZnSO4 (5 mg/kg) or intraperitoneally with LPS (3 mg/kg; Difco; lipopolysaccharide W, Salmonella typhosa 0901). Tissues were removed and MT-I mRNA levels were measured in total nucleic acid samples as desc...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Induction of mouse metallothionein-I mRNA by bacterial endotoxin is independent of metals and glucocorticoid hormones.

Durnam¹,

Hoffman²,

Quaife³

et al. 1984

Proc. Natl. Acad. Sci. U.S.A.

132

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“…transgenic mice than in CETP transgenic mice (20). The mT-CETP transgenic mice were also studied since the mT promoter is upregulated by corticosteroid and LPS (28,29), offering a contrasting response to that in NFR-CETP transgenic mice. As in earlier studies (Fig.…”

Section: Methodsmentioning

confidence: 99%

Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice.

Masucci-Magoulas

Moulin²,

Jiang³

et al. 1995

J. Clin. Invest.

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IntroductionThe plasma cholesteryl ester transfer protein (CETP) mediates the exchange of HDL cholesteryl esters (CE) The metabolism of HDL is regulated, in part, by the activities of lipases and lipid transfer proteins (1). Cholesteryl esters, generated in HDL by lecithin:cholesterol acyltransferase, are exchanged with triglycerides of VLDL, as a result of the activity of cholesteryl ester transfer protein (CETP)'. The subsequent activity of hepatic lipase on triglyceride-enriched HDL results in a decrease in HDL size and catabolism of the major apoliprotein of HDL, apoA-I (2). In a striking demonstration of the interaction of hypertriglyceridemia with cholesteryl ester transfer processes, hypertriglyceridemic apoC-II transgenic mice show profound reductions in HDL cholesterol and apoA-I when crossed with human CETP/apoA-I transgenic mice, to produce apoA-I/CETP/apoC-llH transgenic mice (3). In addition to plasma triglyceride concentration, effective plasma CETP activity is also influenced by changes in CETP concentration, such as those resulting from changes in dietary cholesterol or probucol therapy (4, 5).HDL is thought to mediate the reverse transport of cholesterol from peripheral tissues to the liver (6). In addition to this well-known role, Ulevitch et al. (7) have suggested another, novel function for HDL, namely to bind bacterial lipopolysaccharide (endotoxin) and thereby to modulate its biological effects. The binding of endotoxin to HDL can prevent endotoxininduced death (8). Harris et al. (9) have shown that VLDL and chylomicrons can also bind endotoxin, and protect mice against endotoxin-induced death. However, the potency of HDL appeared to be greater than that of other lipoproteins (9), and the molar concentrations of HDL in plasma are usually higher than other lipoproteins. Another role of HDL may be to provide cholesterol for adrenal corticosteroid synthesis ( 10-12), a function that could be particularly important during stress (13).The purpose of the present study was to examine the possible regulation of CETP gene expression in response to LPS administration. We suspected that CETP might be altered by LPS, since LPS has profound effects on lipoprotein metabolism and is known to regulate lipoprotein lipase and LCAT activities ( 14,15

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“…In rats and Syrian hamsters, endotoxin treatment increases Zn and decreases Cu concentrations in liver and decreases Zn and increases Cu concentrations in plasma (6,7). At the cellular level, endotoxin treatment increases the amount of Zn bound to MT, a cytosolic transition metal-binding protein, in the liver (8) and in cultured hepatocytes (9) and increases the urinary excretion of MT (10). Induction of MT synthesis protects macrophages against endotoxin-induced cell killing (I 1).…”

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confidence: 99%

Altered Organ Growth and Zinc and Copper Distribution in Endotoxin-Treated Neonatal Mice

Thomas

Winchurch

1991

Pediatr Res

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Abbreviations essential metals, Zn and Cu. In rats and Syrian hamsters, endotoxin treatment increases Zn and decreases Cu concentrations in liver and decreases Zn and increases Cu concentrations in plasma (6, 7). At the cellular level, endotoxin treatment increases the amount of Zn bound to MT, a cytosolic transition metal-binding protein, in the liver (8) and in cultured hepatocytes (9) and increases the urinary excretion of MT (10). Induction of MT synthesis protects macrophages against endotoxin-induced cell killing (I 1). A distinct 5' regulatory site uniquely responsive to endotoxin modulates MT-I gene transcription in mouse liver and kidney (12).The objective of the present study was to examine changes in tissue growth and Zn and Cu distribution that accompany exposure to endotoxin in early life. Because endotoxin increases MT gene transcription (6, 7) and because this protein sequesters both Zn and Cu intracellularly (13), the possibility that changes in the Zn and Cu distribution among tissues and their binding to MT were associated with endotoxin exposure was investigated. Thymic growth in endotoxin-treated neonatal mice was examined, because decreased Zn and Cu bioavailability either in utero or in early postnatal life can affect thymic growth and development and diminish immunoresponsiveness (1 4-18). Because the liver is the major depot for both Zn and Cu in the neonate and MT is a major intracellular ligand for these metals in the neonatal liver (19)(20)(21), it was of interest to determine the role of MT induction by endotoxin in the accumulation of these metals in liver and their binding to MT in this organ. MATERIALS AND METHODS MT, metallothioneinMale and female HLA/ICR mice (Hill Top Lab Animals, LPS, Serratia marcescens lipopolysaccharide W Scottdale, PA) were paired overnight and maintained with free access to rodent food (Agway, Syracuse, NY) and tap water in a 12 h light-12 h dark photocycle at 23°C. Pregnant females were caged singly before parturition and day of delivery was designated as d 0. Litters were reduced to six pups within 24 h of birth and Endotoxins are complex li~o~ol~saccharides derived from cell pups were always maintained with free access to lactating dams. walls of gram-negative bacteria (1). These toxins have a wide ~p s (no. 3130-35, lot 565368; Difco, Detroit, MI) was disrange of ~a t h o~h~s i o l o g i c effects (2) and play significant roles in solved in physiologic saline and sterilized by filtration immedithe development of circulatory shock (3). These effects are me-ately before use. At 2 d of age, LPS-treated mice received 10 pg diated in part by endotoxin-stimulated production and release of LPS intraperitoneally in 0.05 mL; age-matched control mice of acute phase cytokines (4) and by endotoxin-de~endent mod-received intraperitoneal injections of 0.05 mL of sterile physioulation of glucocorticoid hormone action (5). Endotoxin expo-logic saline. ~t 5, 7, 14, and 28 d of age, LPS-and saline-treated sure also alters the systemic and intracellular metabolism of the...

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Hepatic Metallothionein Induction in Inflammation*†

Cited by 54 publications

References 28 publications

Induction of mouse metallothionein-I mRNA by bacterial endotoxin is independent of metals and glucocorticoid hormones.

Induction of mouse metallothionein-I mRNA by bacterial endotoxin is independent of metals and glucocorticoid hormones.

Decreased cholesteryl ester transfer protein (CETP) mRNA and protein and increased high density lipoprotein following lipopolysaccharide administration in human CETP transgenic mice.

Altered Organ Growth and Zinc and Copper Distribution in Endotoxin-Treated Neonatal Mice

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