Abstract
The purpose of the present study was to assess the influence of age and acute infection on the production of Hsp32 in human peripheral blood cells, using flow cytometry. Thirty-five controls and 31 patients with acute infection participated. We found that the age and inflammatory status correlated positively with Hsp32 levels in both heat shocked (HS) and non-HS monocytes and lymphocytes. In addition, the HS response of Hsp32 was different in these peripheral blood cells; whereas HS exerted an up-regulation in the levels of Hsp32 in monocytes, a significant decrease in Hsp32 levels was noticed for lymphocytes. We found significant relationships between circulating C-reactive protein as well as interleukin-6 and the levels of Hsp32 in cells. We conclude that Hsp32 is up-regulated in the elderly as well as in individuals with inflammation, and that the HS response of Hsp32 is different in monocytes as compared to lymphocytes.
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Schlesinger MJ, Ashburner M, Tissieres A: Heat Shock from Bacteria to Man. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory, 1982
Sorger PK, Pelham HR: Cloning and expression of a gene encoding hsc73, the major hsp70-like protein in unstressed rat cells. EMBO J 6:993–998, 1987
O’Malley K, Mauron A, Barchas JD, Kedes L: Constitutively expressed rat mRNA encoding a 70-kilodalton heat-shock-like protein. Mol Cell Biol 5:3476–3483, 1985
Haire RN, Peterson MS, O’Leary JJ: Mitogen activation induces the enhanced synthesis of two heat-shock proteins in human lymphocytes. J Cell Biol 106:883–891, 1988
Twomey BM, McCallum S, Isenberg DA, Latchman DS: Elevation of heat shock protein synthesis and hsp gene transcription during monocyte to macrophage differentiation of U937 cells. Clin Exp Immunol 93:178–183, 1993
Richards FM, Watson A, Hickman JA: Investigation of the effects of heat shock and agents which induce a heat shock response on the induction of differentiation of HL-60 cells. Cancer Res 48:6715–6720, 1988
Kao HT, Capasso O, Heintz N, Nevins JR: Cell cycle control of the human HSP70 gene: Implications for the role of a cellular E1A-like function. Mol Cell Biol 5:628–633, 1985
Bensaude O, Babinet C, Morange M, Jacob F: Heat shock proteins, first major products of zygotic gene activity in mouse embryo. Nature 305:331–3, 1983
Njemini R, Abeele MV, Demanet C, Lambert M, Vandebosch S, Mets T: Age-related decrease in the inducibility of heat-shock protein 70 in human peripheral blood mononuclear cells. J Clin Immunol 22:195–205, 2002
Tanaka K, Jay G, Isselbacher KJ: Expression of heat-shock and glucose-regulated genes: Differential effects of glucose starvation and hypertonicity. Biochim Biophys Acta 950:138–146, 1988
Chi NC, Karliner JS: Molecular determinants of responses to myocardial ischemia/reperfusion injury: Focus on hypoxia-inducible and heat shock factors. Cardiovasc Res 61:437–447, 2004
Hammerer-Lercher A, Mair J, Bonatti J, Watzka SB, Puschendorf B, Dirnhofer S: Hypoxia induces heat shock protein expression in human coronary artery bypass grafts. Cardiovasc Res 50:115–124, 2001
Jaattela M, Wissing D: Heat-shock proteins protect cells from monocyte cytotoxicity: Possible mechanism of self-protection. J Exp Med 177:231–236, 1993
Georgopoulos C, Welch WJ: Role of the major heat shock proteins as molecular chaperones. Annu Rev Cell Biol 9:601–634, 1993
Welch WJ: Heat shock proteins functioning as molecular chaperones: Their roles in normal and stressed cells. Philos Trans R Soc Lond B Biol Sci 339:327–333, 1993
Feder ME, Hofmann GE: Heat-shock proteins, molecular chaperones, and the stress response: Evolutionary and ecological physiology. Annu Rev Physiol 61:243–82, 1999
Tenhunen R, Marver HS, Schmid R: The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 61:748–755, 1968
Applegate LA, Luscher P, Tyrrell RM: Induction of heme oxygenase: a general response to oxidant stress in cultured mammalian cells. Cancer Res 51:974–978, 1991
Nath KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME: Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest 90:267–270, 1992
Yachie A, Niida Y, Wada T, Igarashi N, Kaneda H, Toma T, Ohta K, Kasahara Y, Koizumi S: Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J Clin Invest 103:129–135, 1999
Rensing H, Bauer I, Datene V, Patau C, Pannen BH, Bauer M: Differential expression pattern of heme oxygenase-1/heat shock protein 32 and nitric oxide synthase-II and their impact on liver injury in a rat model of hemorrhage and resuscitation. Crit Care Med 27:2766–27675, 1999
Lee TS, Tsai HL, Chau LY: Induction of heme oxygenase-1 expression in murine macrophages is essential for the anti-inflammatory effect of low dose 15-deoxy-Delta 12,14-prostaglandin J2. J Biol Chem 278:19325–19330, 2003
Guo X, Shin VY, Cho CH: Modulation of heme oxygenase in tissue injury and its implication in protection against gastrointestinal diseases. Life Sci 69:3113–3119, 2001
Llesuy SF, Tomaro ML: Heme oxygenase and oxidative stress. Evidence of involvement of bilirubin as physiological protector against oxidative damage. Biochim Biophys Acta 1223:9–14, 1994
McCoubrey WK Jr, Huang TJ, Maines MD: Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3. Eur J Biochem 247:725–732, 1997
Cruse I, Maines MD: Evidence suggesting that the two forms of heme oxygenase are products of different genes. J Biol Chem 263:3348–3353, 1988
Maines MD, Mayer RD, Ewing JF, McCoubrey WK Jr: Induction of kidney heme oxygenase-1 (HSP32) mRNA and protein by ischemia/reperfusion: possible role of heme as both promotor of tissue damage and regulator of HSP32. J Pharmacol Exp Ther 264:457–462, 1993
Bauer M, Pannen BH, Bauer I, Herzog C, Wanner GA, Hanselmann R, Zhang JX, Clemens MG, Larsen R: Evidence for a functional link between stress response and vascular control in hepatic portal circulation. Am J Physiol 271:929–935, 1996
Sonin NV, Garcia-Pagan JC, Nakanishi K, Zhang JX, Clemens MG: Patterns of vasoregulatory gene expression in the liver response to ischemia/reperfusion and endotoxemia. Shock 11:175–179, 1999
Choi AM, Alam J: Heme oxygenase-1: Function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury. Am J Respir Cell Mol Biol 15:9–19, 1996
Zayasu K, Sekizawa K, Okinaga S, Yamaya M, Ohrui T, Sasaki H: Increased carbon monoxide in exhaled air of asthmatic patients. Am J Respir Crit Care Med 156:1140–1143, 1997
Murphy BJ, Laderoute KR, Short SM, Sutherland RM: The identification of heme oxygenase as a major hypoxic stress protein in Chinese hamster ovary cells. Br J Cancer 64:69–73, 1991
Keyse SM, Tyrrell RM: Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci USA 86:99–103, 1989
Taketani S, Kohno H, Yoshinaga T, Tokunaga R: The human 32-kDa stress protein induced by exposure to arsenite and cadmium ions is heme oxygenase. FEBS Lett 245:173–176, 1989
Shibahara S, Muller RM, Taguchi H: Transcriptional control of rat heme oxygenase by heat shock. J Biol Chem 262:12889–12892, 1987
Finkel T, Holbrook NJ: Oxidants, oxidative stress and the biology of ageing. Nature 408:239–247, 2000
Hamilton ML, Van Remmen H, Drake JA, Yang H, Guo ZM, Kewitt K, Walter CA, Richardson A: Does oxidative damage to DNA increase with age? Proc Natl Acad Sci USA 98:10469–10474, 2001
Golden TR, Melov S: Mitochondrial DNA mutations, oxidative stress, and aging. Mech Ageing Dev 122:1577–1589, 2001
Stadtman ER: Protein oxidation and aging. Science 257:1220–1224, 1992
Mandavilli BS, Santos JH, Van Houten B: Mitochondrial DNA repair and aging. Mutat Res 509:127–151, 2002
Bokov A, Chaudhuri A, Richardson A: The role of oxidative damage and stress in aging. Mech Ageing Dev 125:811–826, 2004
Stadtman ER: Protein oxidation in aging and age-related diseases. Ann N Y Acad Sci 928:22–38, 2001
Hagen TM: Oxidative stress, redox imbalance, and the aging process. Antioxid Redox Signal 5:503–6, 2003
Beal MF: Oxidatively modified proteins in aging and disease. Free Radic Biol Med 32:797–803, 2002
Sohal RS: Role of oxidative stress and protein oxidation in the aging process. Free Radic Biol Med 33:37–44, 2002
Drew B, Leeuwenburgh C: Aging and the role of reactive nitrogen species. Ann N Y Acad Sci 959:66–81, 2002
Tien M, Berlett BS, Levine RL, Chock PB, Stadtman ER: Peroxynitrite-mediated modification of proteins at physiological carbon dioxide concentration: pH dependence of carbonyl formation, tyrosine nitration, and methionine oxidation. Proc Natl Acad Sci USA 96:7809–14, 1999
Lavrovsky Y, Song CS, Chatterjee B, Roy AK: Age-dependent increase of heme oxygenase-1 gene expression in the liver mediated by NFkappaB. Mech Ageing Dev 114:49–60, 2000
Iijima N, Tamada Y, Hayashi S, Tanaka M, Ishihara A, Hasegawa M, Ibata Y: Expanded expression of heme oxygenase-1 (HO-1) in the hypothalamic median eminence of aged as compared with young rats: An immunocytochemical study. Neurosci Lett 271:113–116, 1999
Hirose W, Ikematsu K, Tsuda R: Age-associated increases in heme oxygenase-1 and ferritin immunoreactivity in the autopsied brain. Leg Med 5:360–366, 2003
Gardner ID. The effect of aging on susceptibility to infection. Rev Infect Dis 2:801–10, 1980
Ferrucci L, Guralnik JM, Studenski S, Fried LP, Cutler GB Jr, Walston JD: Interventions on Frailty Working Group. Designing randomized, controlled trials aimed at preventing or delaying functional decline and disability in frail, older persons: A consensus report. J Am Geriatr Soc 52:625–634, 2004
Keyse SM, Tyrrell RM. Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite. Proc Natl Acad Sci USA 86:99–103, 1989
Bechoua S, Dubois M, Dominguez Z, Goncalves A, Nemoz G, Lagarde M, Prigent AF: Protective effect of docosahexaenoic acid against hydrogen peroxide-induced oxidative stress in human lymphocytes. Biochem Pharmacol 57:1021–30, 1999
Njemini R, Lambert M, Demanet C, Vanden Abeele M, Vandebosch S, Mets T: The induction of heat shock protein 70 in peripheral mononuclear blood cells in elderly patients: A role for inflammatory markers. Hum Immunol 64:575–585, 2003
Maly FE, Nakamura M, Gauchat JF, Urwyler A, Walker C, Dahinden CA, Cross AR, Jones OT, de Weck AL: Superoxide-dependent nitroblue tetrazolium reduction and expression of cytochrome b-245 components by human tonsillar B lymphocytes and B cell lines. J Immunol 142:1260–1267, 1989
Orie NN, Zidek W, Tepel M: Tyrosine and calcium/calmodulin kinases are common signaling components in the generation of reactive oxygen species in human lymphocytes. Life Sci 65:2135–2142, 1999
Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS: Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J Exp Med 195:59–70, 2002
Lee PJ, Camhi SL, Chin BY, Alam J, Choi AM: AP-1 and STAT mediate hyperoxia-induced gene transcription of heme oxygenase-1. Am J Physiol Lung Cell Mol Physiol 279:175–182, 2000
Kurata S, Matsumoto M, Tsuji Y, Nakajima H: Lipopolysaccharide activates transcription of the heme oxygenase gene in mouse M1 cells through oxidative activation of nuclear factor kappa B. Eur J Biochem 239:566–571, 1996
Peng J, Jones GL, Watson K: Stress proteins as biomarkers of oxidative stress: Effects of antioxidant supplements. Free Radic Biol Med 28:1598–1606, 2000
Unno K, Asakura H, Shibuya Y, Kaiho M, Okada S, Oku N: Increase in basal level of Hsp70, consisting chiefly of constitutively expressed Hsp70 (Hsc70) in aged rat brain. J Gerontol A Biol Sci Med Sci 55:329–35, 2000
Maiello M, Boeri D, Sampietro L, Pronzato MA, Odetti P, Marinari UM: Basal synthesis of heat shock protein 70 increases with age in rat kidneys. Gerontology 44:15–20, 1998
King V, Tower J: Aging-specific expression of Drosophila hsp22. Dev Biol 207:107–18, 1999
Levere RD, Staudinger R, Loewy G, Kappas A, Shibahara S, Abraham NG: Elevated levels of heme oxygenase-1 activity and mRNA in peripheral blood adherent cells of acquired immunodeficiency syndrome patients. Am J Hematol 43:19–23, 1993
Zampetaki A, Minamino T, Mitsialis SA, Kourembanas S: Effect of heme oxygenase-1 overexpression in two models of lung inflammation. Exp Biol Med 228:442–446, 2003
Ohta K, Kikuchi T, Arai S, Yoshida N, Sato A, Yoshimura N: Protective role of heme oxygenase-1 against endotoxin-induced uveitis in rats. Exp Eye Res 77:665–673, 2003
Otterbein LE, Choi AM: Heme oxygenase: colors of defense against cellular stress. Am J Physiol Lung Cell Mol Physiol 279:1029–1037, 2000
Vachharajani TJ, Work J, Issekutz AC, Granger DN: Heme oxygenase modulates selectin expression in different regional vascular beds. Am J Physiol Heart Circ Physiol 278:1613–1617, 2000
Wagener FA, Eggert A, Boerman OC, Oyen WJ, Verhofstad A, Abraham NG, Adema G, van Kooyk Y, de Witte T, Figdor CG: Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 98:1802–1811, 2001
Minamino T, Christou H, Hsieh CM, Liu Y, Dhawan V, Abraham NG, Perrella MA, Mitsialis SA, Kourembanas S: Targeted expression of heme oxygenase-1 prevents the pulmonary inflammatory and vascular responses to hypoxia. Proc Natl Acad Sci USA 98:8798–8803, 2001
Otterbein LE, Bach FH, Alam J, Soares M, Tao Lu H, Wysk M, Davis RJ, Flavell RA, Choi AM: Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 6:422–428, 2000
Reeve VE, Tyrrell RM. Heme oxygenase induction mediates the photoimmunoprotective activity of UVA radiation in the mouse. Proc Natl Acad Sci USA 96:9317–21, 1999
Eisenstein RS, Garcia-Mayol D, Pettingell W, Munro HN. Regulation of ferritin and heme oxygenase synthesis in rat fibroblasts by different forms of iron. Proc Natl Acad Sci USA 88:688–92, 1991
Lavrovsky Y, Schwartzman ML, Levere RD, Kappas A, Abraham NG. Identification of binding sites for transcription factors NF-kappa B and AP-2 in the promoter region of the human heme oxygenase 1 gene. Proc Natl Acad Sci USA 91:5987–91, 1994
Abraham NG, Lavrovsky Y, Schwartzman ML, Stoltz RA, Levere RD, Gerritsen ME, Shibahara S, Kappas A. Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effect against heme and hemoglobin toxicity. Proc Natl Acad Sci USA 92:6798–802, 1995
Suttner DM, Sridhar K, Lee CS, Tomura T, Hansen TN, Dennery PA. Protective effects of transient HO-1 overexpression on susceptibility to oxygen toxicity in lung cells. Am J Physiol 276:443–51, 1999
Yamada N, Yamaya M, Okinaga S, Lie R, Suzuki T, Nakayama K, Takeda A, Yamaguchi T, Itoyama Y, Sekizawa K, Sasaki H. Protective effects of heme oxygenase-1 against oxidant-induced injury in the cultured human tracheal epithelium. Am J Respir Cell Mol Biol 21:428–35, 1999
Elouil H, Cardozo AK, Eizirik DL, Henquin JC, Jonas JC. High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NFkappaB. Diabetologia 48:496–505, 2005
Johnson WT, DeMars LC. Increased heme oxygenase-1 expression during copper deficiency in rats results from increased mitochondrial generation of hydrogen peroxide. J Nutr 134:1328–33, 2004
Lautier D, Luscher P, Tyrrell RM. Endogenous glutathione levels modulate both constitutive and UVA radiation/hydrogen peroxide inducible expression of the human heme oxygenase gene. Carcinogenesis 13:227–32, 1992
Flegar-Mestric Z, Nazor A, Jagarinec N: Haematological profile in healthy urban population (8 to 70 years of age). Coll Antropol 24:185–196, 2000
Strasser A, Teltscher A, May B, Sanders C, Niedermuller H: Age-associated changes in the immune system of German shepherd dogs. J Vet Med A Physiol Pathol Clin Med 47:181–192, 2000
Rochman H: Hematology. In Clinical Pathology in the Elderly. A Textbook of Laboratory Interpretations, H Rochman, MM Lubran, B.A Bradlow (eds). Basel, Karger AG, 1988, pp 142–152
Poss KD, Tonegawa S: Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA 94:10925–10930, 1997
Poss KD, Tonegawa S: Heme oxygenase 1 is required for mammalian iron reutilization. Proc Natl Acad Sci USA 94:10919–10924, 1997
Naito Y, Takagi T, Yoshikawa T: Heme oxygenase-1: A new therapeutic target for inflammatory bowel disease. Aliment Pharmacol Ther 20:177–184, 2004
Abraham NG: Therapeutic applications of human heme oxygenase gene transfer and gene therapy. Curr Pharm Des 9:2513–2524, 2003
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Njemini, R., Lambert, M., Demanet, C. et al. Heat Shock Protein 32 in Human Peripheral Blood Mononuclear Cells: Effect of Aging and Inflammation. J Clin Immunol 25, 405–417 (2005). https://doi.org/10.1007/s10875-005-5361-y
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DOI: https://doi.org/10.1007/s10875-005-5361-y