Cell Stress and Chaperones

, Volume 20, Issue 6, pp 1013–1022 | Cite as

Metallothionein differentially affects the host response to Listeria infection both with and without an additional stress from cold-restraint

  • Rebecca T. Emeny
  • Jane Kasten-Jolly
  • Tapan Mondal
  • Michael A. Lynes
  • David A. Lawrence
Original Paper

Abstract

Acute stress alters anti-bacterial defenses, but the neuroimmunological mechanisms underlying this association are not yet well understood. Metallothionein (MT), a cysteine-rich protein, is a stress response protein that is induced by a variety of chemical, biological, and psychological stressors, and MT has been shown to influence immune activities. We investigated MT’s role in the management of anti-bacterial responses that occur during stress, using a C57BL/6 (B6) strain that has targeted disruptions of the Mt1 and Mt2 genes (B6-MTKO), and a B6 strain that has additional copies of Mt (B6-MTTGN). The well-characterized listeriosis model was used to examine immune mechanisms that are altered by a 1-h stress treatment (cold-restraint, CR) administered just prior to bacterial infection. Intriguingly, MT gene doses both greater and lower than that of wild-type (WT) B6 mice were associated with improved host defenses against Listeria monocytogenes (LM). This augmented protection was diminished by CR stress in the MTKO mice, but transgenic mice with additional MT copies had no CR stress-induced increase in their listerial burden. During the transition from innate to adaptive immunity, on day 3 after infection, oxidative burst and apoptosis were assessed by flow cytometric methods, and cytokine transcription was measured by real-time quantitative PCR. MT gene expression and CR-stress affected the expression of IL-6 and TNFα. Additionally, these genetic and environmental modulations altered the generation of ROS responses as well as the number of apoptotic cells in livers and spleens. Although the level of MT altered the listerial response, MT expression was equally elevated by listerial infection with or without CR stress. These results indicate the ability of MT to regulate immune response mechanisms and demonstrate that increased amounts of MT can eliminate the immunosuppression induced by CR.

Keywords

Metallothionein Infection Listeria Apoptosis Oxidative stress 

References

  1. Borghesi LA, Youn J, Olson EA, Lynes MA (1996) Interactions of metallothionein with murine lymphocytes: plasma membrane binding and proliferation. Toxicology 108(1-2):129–140CrossRefPubMedGoogle Scholar
  2. Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, Vandesompele J, Wittwer CT (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622CrossRefPubMedGoogle Scholar
  3. Cao L, Filipov NM, Lawrence DA (2002) Sympathetic nervous system plays a major role in acute cold/restraint stress inhibition of host resistance to Listeria monocytogenes. J Neuroimmunol 125:94–102CrossRefPubMedGoogle Scholar
  4. Cao L, Hudson CA, Lawrence DA (2003a) Immune changes during acute cold/restraint stress-induced inhibition of host resistance to Listeria. Toxicol Sci 74:325–334CrossRefPubMedGoogle Scholar
  5. Cao L, Hudson CA, Lawrence DA (2003b) Acute cold/restraint stress inhibits host resistance to Listeria monocytogenes via beta1-adrenergic receptors. Brain Behav Immun 17:121–133CrossRefPubMedGoogle Scholar
  6. Canpolat E, Lynes MA (2001) In vivo manipulation of endogenous metallothionein with a monoclonal antibody enhances a T-dependent humoral immune response. Toxicol Sci 62:61–70CrossRefPubMedGoogle Scholar
  7. Carlomagno MA, Coghlan LG, McMurray DN (1986) Chronic zinc deficiency and listeriosis in rats: acquired cellular resistance and response to vaccination. Med Microbiol Immunol 175:271–280CrossRefPubMedGoogle Scholar
  8. Crowthers KC, Kline V, Giardina C, Lynes MA (2000) Augmented humoral immune function in metallothionein-null mice. Toxicol Appl Pharmacol 166:161–172CrossRefPubMedGoogle Scholar
  9. Dai ZK, Qin JK, Huang JE, Luo Y, Xu Q, Zhao HL (2012) Tanshinone IIA activates calcium-dependent apoptosis signaling pathway in human hepatoma cells. J Nat Med 66(1):192–201CrossRefPubMedGoogle Scholar
  10. Devisscher L, Hindryckx P, Lynes M, Waeytens A, Cuvelier C, De Vos F, Vanhove C, De Vos M, Laukens D (2014) Role of metallothioneins as danger signals in the pathogenesis of colitis. J Pathol 233:89–100CrossRefPubMedGoogle Scholar
  11. Dyatlov VA, Lawrence DA (2002) Neonatal lead exposure potentiates sickness behavior induced by Listeria monocytogenes infection of mice. Brain Behav Immun 16:477–492CrossRefPubMedGoogle Scholar
  12. Emeny RT, Gao D, Lawrence DA (2007) Beta1-adrenergic receptors on immune cells impair innate defenses against Listeria. J Immunol 178:4876–4884CrossRefPubMedGoogle Scholar
  13. Emeny RT, Lawrence DA (2007) Cold-restraint-induced immune and biochemical changes inhibit host resistance to Listeria. In: Ader R (ed) Psychoneuroimmunology, Vol 2, 4th edn. Elsevier Academic Press, London, pp 1035–1053CrossRefGoogle Scholar
  14. Emeny RT, Marusov G, Lawrence DA, Pederson-Lane J, Yin X, Lynes MA (2009) Manipulations of metallothionein gene dose accelerate the response to Listeria monocytogenes. Chem Biol Interact 181(2):243–253CrossRefPubMedGoogle Scholar
  15. Ghoshal K, Jacob ST (2001) Regulation of metallothionein gene expression. Prog Nucleic Acid Res Mol Biol 66:357–384CrossRefPubMedGoogle Scholar
  16. Harden LM, du Plessis I, Poole S, Laburn HP (2008) Interleukin (IL)-6 and IL-1 beta act synergistically within the brain to induce sickness behavior and fever in rats. Brain Behav Immun 22:838–849CrossRefPubMedGoogle Scholar
  17. Hernández J, Carrasco J, Belloso E, Giralt M, Bluethmann H, Kee Lee D, Andrews GK, Hidalgo J (2000) Metallothionein induction by restraint stress: role of glucocorticoids and IL-6. Cytokine 12:791–796CrossRefPubMedGoogle Scholar
  18. Hidalgo J, Armario A, Flos R, Dingman A, Garvey JS (1986) The influence of restraint stress in rats on metallothionein production and corticosterone and glucagon secretion. Life Sci 39(7):611–616CrossRefPubMedGoogle Scholar
  19. Inoue K, Takano H, Shimada A, Satoh M (2009) Metallothionein as an anti-inflammatory mediator. Mediators Inflamm 2009:101659. doi:10.1155/2009/101659 PubMedCentralPubMedGoogle Scholar
  20. Hu N, Han X, Lane EK, Gao F, Zhang Y, Ren J (2013) Cardiac-specific overexpression of metallothionein rescues against cigarette smoking exposure-induced myocardial contractile and mitochondrial damage. PLoS One 8(2):e57151PubMedCentralCrossRefPubMedGoogle Scholar
  21. Kent S, Bluthé RM, Kelley KW, Dantzer R (1992) Sickness behavior as a new target for drug development. Trends Pharmacol Sci 13:24–28CrossRefPubMedGoogle Scholar
  22. Kelley KW, Bluthé RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, Broussard SR (2003) Cytokine-induced sickness behavior. Brain Behav Immun 17(Suppl 1):S112–S118CrossRefPubMedGoogle Scholar
  23. Kim D, Reilly A, Lawrence DA (2001) Relationships between IFNgamma, IL-6, corticosterone, and Listeria monocytogenes pathogenesis in BALB/c mice. Cell Immunol 207:13–18CrossRefPubMedGoogle Scholar
  24. Laukens D, Waeytens A, De Bleser P, Cuvelier C, De Vos M (2009) Human metallothionein expression under normal and pathological conditions: mechanisms of gene regulation based on in silico promoter analysis. Crit Rev Eukaryot Gene Expr 19(4):301–317CrossRefPubMedGoogle Scholar
  25. Loukili N, Rosenblatt-Velin N, Rolli J, Levrand S, Feihl F, Waeber B, Pacher P, Liaudet L (2010) Oxidants positively or negatively regulate nuclear factor kappaB in a context-dependent manner. J Biol Chem 285:15746–15752PubMedCentralCrossRefPubMedGoogle Scholar
  26. Lynes MA, Borghesi LA, Youn J, Olson EA (1993) Immunomodulatory activities of extracellular metallothionein. I. Metallothionein effects on antibody production. Toxicology 85:161–177CrossRefPubMedGoogle Scholar
  27. Lynes MA, Garvey JS, Lawrence DA (1990) Extracellular effects of metallothionein on lymphocyte activities. Mol Immunol 27:211–219CrossRefPubMedGoogle Scholar
  28. Lynes MA, Richardson CA, McCabe R, Crowthers KC, Lee JC, Youn J, Schweitzer IB, Shultz LD (1999) In: MT IV Klaassen C (ed) Metallothionein-mediated changes in cell populations of autoimmune mice. Birkhauser Verlag, Basel, pp 437–444Google Scholar
  29. Lynes MA, Zaffuto K, Unfricht DW, Marusov G, Samson JS, Yin X (2006) The physiological roles of extracellular metallothionein. Exp Biol Med (Maywood) 231(9):1548–1554Google Scholar
  30. Manuel Y, Thomas Y, Pellegrini O (1992) Metallothionein and tissue damage. IARC Sci Publ 118:231–237PubMedGoogle Scholar
  31. Maret W (2011) Redox biochemistry of mammalian metallothioneins. J Biol Inorg Chem 16(7):1079–1086CrossRefPubMedGoogle Scholar
  32. Masters BA, Quaife CJ, Erickson JC, Kelly EJ, Froelick GJ, Zambrowicz BP, Brinster RL, Palmiter RD (1994) Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J Neurosci 14:5844–5857PubMedGoogle Scholar
  33. Mondal TK, Li D, Swami K, Dean JK, Hauer C, Lawrence DA (2005) Mercury impairment of mouse thymocyte survival in vitro: involvement of cellular thiols. J Toxicol Environ Health A 68:535–556CrossRefPubMedGoogle Scholar
  34. Palmiter RD, Sandgren EP, Koeller DM, Brinster RL (1993) Distal regulatory elements from the mouse metallothionein locus stimulate gene expression in transgenic mice. Mol Cell Biol 13:5266–5275PubMedCentralCrossRefPubMedGoogle Scholar
  35. Pare WP, Glavin GB (1986) Restraint stress in biomedical research: a review. Neurosci Biobehav Rev 10:339–370CrossRefPubMedGoogle Scholar
  36. Poston RM, Kurlander RJ (1992) Cytokine expression in vivo during murine listeriosis. Infection with live, virulent bacteria is required for monokine and lymphokine messenger RNA accumulation in the spleen. J Immunol 149:3040–3044PubMedGoogle Scholar
  37. Raymond AD, Gekonge B, Giri MS, Hancock A, Papasavvas E, Chehimi J, Kossenkov AV, Nicols C, Yousef M, Mounzer K, Shull J, Kostman J, Showe L, Montaner LJ (2010) Increased metallothionein gene expression, zinc, and zinc-dependent resistance to apoptosis in circulating monocytes during HIV viremia. J Leukoc Biol 88(3):589–596PubMedCentralCrossRefPubMedGoogle Scholar
  38. Ren M, Wang YM, Zhao J, Zhao J, Zhao ZM, Zhang TF, He J, Ren SP, Peng SQ (2014) Metallothioneins attenuate paraquat-induced acute lung injury in mice through the mechanisms of anti-oxidation and anti-apoptosis. Food Chem Toxicol 73:140–147CrossRefPubMedGoogle Scholar
  39. Schell RF, Lawrence DA (1977) Differential effects of concanavalin A and phytohemagglutinin on murine immunity. Suppression and enhancement of cell-mediated immunity. Cell Immunol 31:142–154CrossRefPubMedGoogle Scholar
  40. Shubin NJ, Monaghan SF, Ayala A (2011) Anti-inflammatory mechanisms of sepsis. Contrib Microbiol 17:108–124CrossRefPubMedGoogle Scholar
  41. Simmons HF, James RC, Harbison RD, Patel DG, Roberts SM (1991) Examination of the role of catecholamines in hepatic glutathione suppression by cold-restraint in mice. Toxicology 67(1):29–40CrossRefPubMedGoogle Scholar
  42. Torreggiani A, Chatgilialoglu C, Ferreri C, Melchiorre M, Atrian S, Capdevila M (2013) Non-enzymatic modifications in metallothioneins connected to lipid membrane damages: structural and biomimetic studies under reductive radical stress. J Proteomics 92:204–215CrossRefPubMedGoogle Scholar
  43. Unanue ER (1997) Inter-relationship among macrophages, natural killer cells and neutrophils in early stages of Listeria resistance. Curr Opin Immunol 9:35–43CrossRefPubMedGoogle Scholar
  44. Vašák M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16(7):1067–1078CrossRefPubMedGoogle Scholar
  45. Waeytens A, De Vos M, Laukens D (2009) Evidence for a potential role of metallothioneins in inflammatory bowel diseases. Mediat Inflamm 2009:729172. doi:10.1155/2009/729172 CrossRefGoogle Scholar
  46. Webb M (1987) Metallothionein in regeneration, reproduction and development. Experientia Suppl 52:483–498CrossRefPubMedGoogle Scholar
  47. Yang L, Wang J, Yang J, Schamber R, Hu N, Nair S, Xiong L, Ren J (2015) Antioxidant metallothionein alleviates endoplasmic reticulum stress-induced myocardial apoptosis and contractile dysfunction. Free Radic Res 12:1–33Google Scholar
  48. Yin X, Knecht DA, Lynes MA (2005) Metallothionein mediates leukocyte chemotaxis. BMC Immunol 6:21PubMedCentralCrossRefPubMedGoogle Scholar
  49. Youn J, Hwang S-H, Ryoo Z-Y, Lynes MA, Paik DJ, Chung HS, Kim H-Y (2002) Metallothionein suppresses collagen-induced arthritis via induction of TGF-β and downregulation of proinflammatory mediators. Clin Exp Immunol 129:232–239PubMedCentralCrossRefPubMedGoogle Scholar
  50. Zalewski PD, Forbes IJ, Betts WH (1993) Correlation of apoptosis with change in intracellular labile Zn(II) using zinquin [(2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetic acid], a new specific fluorescent probe for Zn(II). Biochem J 296(Pt 2):403–408PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Cell Stress Society International 2015

Authors and Affiliations

  • Rebecca T. Emeny
    • 1
    • 2
  • Jane Kasten-Jolly
    • 1
  • Tapan Mondal
    • 1
  • Michael A. Lynes
    • 3
  • David A. Lawrence
    • 1
  1. 1.Laboratory of Immunology, Wadsworth CenterNew York State Department of HealthAlbanyUSA
  2. 2.Institute of Epidemiology IIHelmholtz Zentrum München - German Research Center for Environmental Health, GmbHNeuherbergGermany
  3. 3.Department of Molecular and Cell BiologyUniversity of ConnecticutStorrsUSA

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