Metallothionein modulates lipopolysaccharide-stimulated tumour necrosis factor expression in mouse peritoneal macrophages.
PDF (204K)
+2 authors
Journal: 2002/February - Biochemical Journal
ISSN: 0264-6021
PUBMED: 11772408
Abstract:
Metallothionein (MT) is a low-molecular-mass, cysteine-rich metal binding protein thought to be involved in the detoxification of heavy metals and scavenging of free radicals. MT is directly induced not only by heavy metals, but also by hormones and cytokines. The present study, which uses mice with genetic deletions of the MT proteins (MT(-/-) mice), was designed to evaluate the effects of MT on the expression of pro-inflammatory cytokines in macrophages. We found that the production of tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS) in peritoneal macrophages is up-regulated by MT via the modulation of nuclear factor kappaB (NF-kappaB) activity. This conclusion is supported by the following observations: (1) LPS stimulated the secretion of less TNF activity from MT(-/-) peritoneal exudate macrophages (PEMs) than from wild-type controls (MT(+/+) mice) without a difference in the pattern of kinetics; (2) LPS-stimulated expression of TNF-alpha mRNA was decreased in MT(-/-) PEMs; (3) LPS-stimulated activation of NF-kappaB was decreased in MT(-/-) PEMs; and (4) production of TNF in PEMs of MT(-/-) mice after LPS treatment in vivo was decreased (compared with MT(+/+) PEMs). Expression of other inflammatory cytokines, interleukin (IL)-1alpha and IL-6 mRNA, which were modulated by NF-kappaB, were also down-regulated in MT(-/-) PEMs. Thus MT plays a key role in the LPS-induced activation of PEMs via the modulation of NF-kappaB activity.
Open in
PUBMED | PMC | Google Scholar | Wikipedia
Relations:
Content
Citations
(6)
References
(50)
Chemicals
(7)
Organisms
(3)
Processes
(2)
Anatomy
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Biochem J 361(Pt 2): 363-369
PMID: 11772408

Metallothionein modulates lipopolysaccharide-stimulated tumour necrosis factor expression in mouse peritoneal macrophages.

Abstract

Metallothionein (MT) is a low-molecular-mass, cysteine-rich metal binding protein thought to be involved in the detoxification of heavy metals and scavenging of free radicals. MT is directly induced not only by heavy metals, but also by hormones and cytokines. The present study, which uses mice with genetic deletions of the MT proteins (MT(-/-) mice), was designed to evaluate the effects of MT on the expression of pro-inflammatory cytokines in macrophages. We found that the production of tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS) in peritoneal macrophages is up-regulated by MT via the modulation of nuclear factor kappaB (NF-kappaB) activity. This conclusion is supported by the following observations: (1) LPS stimulated the secretion of less TNF activity from MT(-/-) peritoneal exudate macrophages (PEMs) than from wild-type controls (MT(+/+) mice) without a difference in the pattern of kinetics; (2) LPS-stimulated expression of TNF-alpha mRNA was decreased in MT(-/-) PEMs; (3) LPS-stimulated activation of NF-kappaB was decreased in MT(-/-) PEMs; and (4) production of TNF in PEMs of MT(-/-) mice after LPS treatment in vivo was decreased (compared with MT(+/+) PEMs). Expression of other inflammatory cytokines, interleukin (IL)-1alpha and IL-6 mRNA, which were modulated by NF-kappaB, were also down-regulated in MT(-/-) PEMs. Thus MT plays a key role in the LPS-induced activation of PEMs via the modulation of NF-kappaB activity.

Full Text

The Full Text of this article is available as a PDF (204K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Kaufmann SH. Heat shock proteins and autoimmunity: a critical appraisal. Int Arch Allergy Immunol. 1994;103(4):317–322. [PubMed] [Google Scholar]
  • Cousins RJ, Leinart AS. Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1. FASEB J. 1988 Oct;2(13):2884–2890. [PubMed] [Google Scholar]
  • Webb M, Verschoyle RD. An investigation of the role of metallothioneins in protection against the acute toxicity of the cadmium ion. Biochem Pharmacol. 1976 Mar 15;25(6):673–679. [PubMed] [Google Scholar]
  • Thomas JP, Bachowski GJ, Girotti AW. Inhibition of cell membrane lipid peroxidation by cadmium- and zinc-metallothioneins. Biochim Biophys Acta. 1986 Dec 10;884(3):448–461. [PubMed] [Google Scholar]
  • Thornalley PJ, Vasák M. Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta. 1985 Jan 21;827(1):36–44. [PubMed] [Google Scholar]
  • Churchich JE, Scholz G, Kwok F. Modulation of the catalytic activity of pyridoxal kinase by metallothionein. Biochem Int. 1988 Sep;17(3):395–403. [PubMed] [Google Scholar]
  • Li TY, Kraker AJ, Shaw CF, 3rd, Petering DH. Ligand substitution reactions of metallothioneins with EDTA and apo-carbonic anhydrase. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6334–6338.[PMC free article] [PubMed] [Google Scholar]
  • Zeng J, Heuchel R, Schaffner W, Kägi JH. Thionein (apometallothionein) can modulate DNA binding and transcription activation by zinc finger containing factor Sp1. FEBS Lett. 1991 Feb 25;279(2):310–312. [PubMed] [Google Scholar]
  • Abdel-Mageed AB, Agrawal KC. Activation of nuclear factor kappaB: potential role in metallothionein-mediated mitogenic response. Cancer Res. 1998 Jun 1;58(11):2335–2338. [PubMed] [Google Scholar]
  • Yagle MK, Palmiter RD. Coordinate regulation of mouse metallothionein I and II genes by heavy metals and glucocorticoids. Mol Cell Biol. 1985 Feb;5(2):291–294.[PMC free article] [PubMed] [Google Scholar]
  • Hager LJ, Palmiter RD. Transcriptional regulation of mouse liver metallothionein-I gene by glucocorticoids. Nature. 1981 May 28;291(5813):340–342. [PubMed] [Google Scholar]
  • Karin M, Imbra RJ, Heguy A, Wong G. Interleukin 1 regulates human metallothionein gene expression. Mol Cell Biol. 1985 Oct;5(10):2866–2869.[PMC free article] [PubMed] [Google Scholar]
  • Schroeder JJ, Cousins RJ. Interleukin 6 regulates metallothionein gene expression and zinc metabolism in hepatocyte monolayer cultures. Proc Natl Acad Sci U S A. 1990 Apr;87(8):3137–3141.[PMC free article] [PubMed] [Google Scholar]
  • Kasutani K, Itoh N, Kanekiyo M, Muto N, Tanaka K. Requirement for cooperative interaction of interleukin-6 responsive element type 2 and glucocorticoid responsive element in the synergistic activation of mouse metallothionein-I gene by interleukin-6 and glucocorticoid. Toxicol Appl Pharmacol. 1998 Jul;151(1):143–151. [PubMed] [Google Scholar]
  • De SK, McMaster MT, Andrews GK. Endotoxin induction of murine metallothionein gene expression. J Biol Chem. 1990 Sep 5;265(25):15267–15274. [PubMed] [Google Scholar]
  • Sato M, Sasaki M, Hojo H. Tissue specific induction of metallothionein synthesis by tumor necrosis factor-alpha. Res Commun Chem Pathol Pharmacol. 1992 Feb;75(2):159–172. [PubMed] [Google Scholar]
  • Leibbrandt ME, Koropatnick J. Activation of human monocytes with lipopolysaccharide induces metallothionein expression and is diminished by zinc. Toxicol Appl Pharmacol. 1994 Jan;124(1):72–81. [PubMed] [Google Scholar]
  • Nathan C. Nitric oxide as a secretory product of mammalian cells. FASEB J. 1992 Sep;6(12):3051–3064. [PubMed] [Google Scholar]
  • Nussler AK, Billiar TR. Inflammation, immunoregulation, and inducible nitric oxide synthase. J Leukoc Biol. 1993 Aug;54(2):171–178. [PubMed] [Google Scholar]
  • Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985 May 1;161(5):984–995.[PMC free article] [PubMed] [Google Scholar]
  • Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ, 3rd, Zentella A, Albert JD, et al. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. [PubMed] [Google Scholar]
  • Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. [PubMed] [Google Scholar]
  • Collart MA, Baeuerle P, Vassalli P. Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B. Mol Cell Biol. 1990 Apr;10(4):1498–1506.[PMC free article] [PubMed] [Google Scholar]
  • Drouet C, Shakhov AN, Jongeneel CV. Enhancers and transcription factors controlling the inducibility of the tumor necrosis factor-alpha promoter in primary macrophages. J Immunol. 1991 Sep 1;147(5):1694–1700. [PubMed] [Google Scholar]
  • Neuschwander-Tetri BA, Bellezzo JM, Britton RS, Bacon BR, Fox ES. Thiol regulation of endotoxin-induced release of tumour necrosis factor alpha from isolated rat Kupffer cells. Biochem J. 1996 Dec 15;320(Pt 3):1005–1010.[PMC free article] [PubMed] [Google Scholar]
  • Wang F, Wang LY, Wright D, Parmely MJ. Redox imbalance differentially inhibits lipopolysaccharide-induced macrophage activation in the mouse liver. Infect Immun. 1999 Oct;67(10):5409–5416.[PMC free article] [PubMed] [Google Scholar]
  • Kanekiyo M, Itoh N, Kawasaki A, Tanaka J, Nakanishi T, Tanaka K. Zinc-induced activation of the human cytomegalovirus major immediate-early promoter is mediated by metallothionein and nuclear factor-kappaB. Toxicol Appl Pharmacol. 2001 Jun 15;173(3):146–153. [PubMed] [Google Scholar]
  • Sakurai A, Hara S, Okano N, Kondo Y, Inoue J, Imura N. Regulatory role of metallothionein in NF-kappaB activation. FEBS Lett. 1999 Jul 16;455(1-2):55–58. [PubMed] [Google Scholar]
  • Masters BA, Kelly EJ, Quaife CJ, Brinster RL, Palmiter RD. Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium. Proc Natl Acad Sci U S A. 1994 Jan 18;91(2):584–588.[PMC free article] [PubMed] [Google Scholar]
  • Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149–154. [PubMed] [Google Scholar]
  • Dignam JD, Lebovitz RM, Roeder RG. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489.[PMC free article] [PubMed] [Google Scholar]
  • Wollenberg GK, DeForge LE, Bolgos G, Remick DG. Differential expression of tumor necrosis factor and interleukin-6 by peritoneal macrophages in vivo and in culture. Am J Pathol. 1993 Oct;143(4):1121–1130.[PMC free article] [PubMed] [Google Scholar]
  • Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. 1997 Apr 10;336(15):1066–1071. [PubMed] [Google Scholar]
  • Leibbrandt ME, Khokha R, Koropatnick J. Antisense down-regulation of metallothionein in a human monocytic cell line alters adherence, invasion, and the respiratory burst. Cell Growth Differ. 1994 Jan;5(1):17–25. [PubMed] [Google Scholar]
  • Crowthers KC, Kline V, Giardina C, Lynes MA. Augmented humoral immune function in metallothionein-null mice. Toxicol Appl Pharmacol. 2000 Aug 1;166(3):161–172. [PubMed] [Google Scholar]
  • Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. [PubMed] [Google Scholar]
  • Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science. 1998 Aug 14;281(5379):1001–1005. [PubMed] [Google Scholar]
  • Tsai EY, Yie J, Thanos D, Goldfeld AE. Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. Mol Cell Biol. 1996 Oct;16(10):5232–5244.[PMC free article] [PubMed] [Google Scholar]
  • Leitman DC, Ribeiro RC, Mackow ER, Baxter JD, West BL. Identification of a tumor necrosis factor-responsive element in the tumor necrosis factor alpha gene. J Biol Chem. 1991 May 25;266(15):9343–9346. [PubMed] [Google Scholar]
  • Verma IM, Stevenson JK, Schwarz EM, Van Antwerp D, Miyamoto S. Rel/NF-kappa B/I kappa B family: intimate tales of association and dissociation. Genes Dev. 1995 Nov 15;9(22):2723–2735. [PubMed] [Google Scholar]
  • Stancovski I, Baltimore D. NF-kappaB activation: the I kappaB kinase revealed? Cell. 1997 Oct 31;91(3):299–302. [PubMed] [Google Scholar]
  • Buchmüller-Rouiller Y, Corrandin SB, Smith J, Schneider P, Ransijn A, Jongeneel CV, Mauël J. Role of glutathione in macrophage activation: effect of cellular glutathione depletion on nitrite production and leishmanicidal activity. Cell Immunol. 1995 Aug;164(1):73–80. [PubMed] [Google Scholar]
  • Deneke SM, Fanburg BL. Regulation of cellular glutathione. Am J Physiol. 1989 Oct;257(4 Pt 1):L163–L173. [PubMed] [Google Scholar]
  • Conrad CC, Grabowski DT, Walter CA, Sabia M, Richardson A. Using MT(-/-) mice to study metallothionein and oxidative stress. Free Radic Biol Med. 2000 Feb 1;28(3):447–462. [PubMed] [Google Scholar]
  • McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969 Nov 25;244(22):6049–6055. [PubMed] [Google Scholar]
  • Driessen C, Hirv K, Kirchner H, Rink L. Zinc regulates cytokine induction by superantigens and lipopolysaccharide. Immunology. 1995 Feb;84(2):272–277.[PMC free article] [PubMed] [Google Scholar]
  • Hirota K, Murata M, Sachi Y, Nakamura H, Takeuchi J, Mori K, Yodoi J. Distinct roles of thioredoxin in the cytoplasm and in the nucleus. A two-step mechanism of redox regulation of transcription factor NF-kappaB. J Biol Chem. 1999 Sep 24;274(39):27891–27897. [PubMed] [Google Scholar]
  • Woo ES, Kondo Y, Watkins SC, Hoyt DG, Lazo JS. Nucleophilic distribution of metallothionein in human tumor cells. Exp Cell Res. 1996 May 1;224(2):365–371. [PubMed] [Google Scholar]
  • Sakurada S, Kato T, Okamoto T. Induction of cytokines and ICAM-1 by proinflammatory cytokines in primary rheumatoid synovial fibroblasts and inhibition by N-acetyl-L-cysteine and aspirin. Int Immunol. 1996 Oct;8(10):1483–1493. [PubMed] [Google Scholar]
  • Yang JP, Merin JP, Nakano T, Kato T, Kitade Y, Okamoto T. Inhibition of the DNA-binding activity of NF-kappa B by gold compounds in vitro. FEBS Lett. 1995 Mar 13;361(1):89–96. [PubMed] [Google Scholar]
Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
Department of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
Copyright notice

Abstract

Metallothionein (MT) is a low-molecular-mass, cysteine-rich metal binding protein thought to be involved in the detoxification of heavy metals and scavenging of free radicals. MT is directly induced not only by heavy metals, but also by hormones and cytokines. The present study, which uses mice with genetic deletions of the MT proteins (MT(-/-) mice), was designed to evaluate the effects of MT on the expression of pro-inflammatory cytokines in macrophages. We found that the production of tumour necrosis factor (TNF) induced by lipopolysaccharide (LPS) in peritoneal macrophages is up-regulated by MT via the modulation of nuclear factor kappaB (NF-kappaB) activity. This conclusion is supported by the following observations: (1) LPS stimulated the secretion of less TNF activity from MT(-/-) peritoneal exudate macrophages (PEMs) than from wild-type controls (MT(+/+) mice) without a difference in the pattern of kinetics; (2) LPS-stimulated expression of TNF-alpha mRNA was decreased in MT(-/-) PEMs; (3) LPS-stimulated activation of NF-kappaB was decreased in MT(-/-) PEMs; and (4) production of TNF in PEMs of MT(-/-) mice after LPS treatment in vivo was decreased (compared with MT(+/+) PEMs). Expression of other inflammatory cytokines, interleukin (IL)-1alpha and IL-6 mRNA, which were modulated by NF-kappaB, were also down-regulated in MT(-/-) PEMs. Thus MT plays a key role in the LPS-induced activation of PEMs via the modulation of NF-kappaB activity.

Abstract
Full Text
Selected References
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.