Gene expression profiling of macrophages: implications for an immunosuppressive effect of dissolucytotic gold ions

Oliver Seifert, Andreas Matussek, Florence Sjögren, Robert Geffers, Chris D Anderson, Oliver Seifert, Andreas Matussek, Florence Sjögren, Robert Geffers, Chris D Anderson

Abstract

Background: Gold salts has previously been used in the treatment of rheumatoid arthritis but have been replaced by biologicals such as TNF-α inhibitors. The mechanisms behind the anti-inflammatory effect of metallic gold ions are still unknown, however, recent data showed that charged gold atoms are released from pure metallic gold implants by macrophages via a dissolucytosis membrane, and that gold ions are taken up by local macrophages, mast cells and to some extent fibroblasts. These findings open the question of possible immunomodulatory effects of metallic gold and motivate efforts on a deeper understanding of the effect of metallic gold on key inflammatory cells as macrophages.

Methods: Human macrophage cells (cell line THP-1) were grown on gold foils and intracellular uptake was analysed by autometallography. The impact of phagocytised gold ions on viability of THP-1 cells was investigated by trypan blue staining and TUNEL assay. The global gene expression profile of THP-1 cells after incorporation of gold ions was studied using microarray analysis comprising approximately 20,000 genes. The gene expression data was confirmed by measurement of secreted proteins.

Results: Autometallography showed intracellular uptake of gold ions into THP-1 cells. No significant effect on viability of THP-1 cells was demonstrated. Our data revealed a unique gene expression signature of dissolucytotic THP-1 cells that had taken up gold ions. A large number of regulated genes were functionally related to immunomodulation. Gold ion uptake induced downregulation of genes involved in rheumatoid arthritis such as hepatocyte growth factor, tenascin-C, inhibitor of DNA binding 1 and 3 and matrix metalloproteinase 13.

Conclusion: The data obtained in this study offer new insights into the mode of action of gold ions and suggest for the investigation of effects on other key cells and a possible future role of metallic gold as implants in rheumatoid arthritis or other inflammatory conditions.

Figures

Figure 1
Figure 1
a: Autometallographic analysis of THP-1 cells cultured without gold contact after 4 days.b: Autometallographic analysis of THP-1 cells grown on gold foils after 4 days. c: Autometallographic analysis of THP-1 cells grown on gold foils after 1, 2 and 3 days.
Figure 2
Figure 2
No significant difference in amount of TUNEL test positive THP-1 cells was seen between cells grown on gold foils and control cells in percent after 4 days (n = 3, p > 0.05).
Figure 3
Figure 3
THP-1 cells grown on gold foils showed significant decreased expression of early growth response 1 (EGR1) protein in cell culture supernatants compared with control cells after 4 days (n = 3, p 

Figure 4

THP-1 cells grown on gold…

Figure 4

THP-1 cells grown on gold foils showed significant decreased expression of lymphotoxin B…

Figure 4
THP-1 cells grown on gold foils showed significant decreased expression of lymphotoxin B (LTB) protein in cell culture supernatants compared with control cells after 4 days (n = 3, p 

Figure 5

THP-1 cells grown on gold…

Figure 5

THP-1 cells grown on gold foils showed significant decreased expression of fatty acid…

Figure 5
THP-1 cells grown on gold foils showed significant decreased expression of fatty acid desaturase 1 (FADS1) protein in cell culture supernatants compared with control cells after 4 days (n = 3, p 
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References
    1. Burmester GR. Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update. Z Rheumatol. 2001;60:167–173. doi: 10.1007/s003930170065. - DOI - PubMed
    1. Simon LS, Yocum D. New and future drug therapies for rheumatoid arthritis. Rheumatol (Oxford) 2000;39(Suppl 1):36–42. doi: 10.1093/oxfordjournals.rheumatology.a031493. - DOI - PubMed
    1. Simon LS. DMARDs in the treatment of rheumatoid arthritis: current agents and future developments. Int J Clin Pract. 2000;54:243–249. - PubMed
    1. Jaeger GT, Larsen S, Soli N, Moe L. Two years follow-up study of the pain-relieving effect of gold bead implantation in dogs with hip-joint arthritis. Acta Vet Scand. 2007;49:9. doi: 10.1186/1751-0147-49-9. - DOI - PMC - PubMed
    1. Canumalla AJ, Al-Zamil N, Phillips M, Isab AA, Shaw CF 3rd. Redox and ligand exchange reactions of potential gold(I) and gold(III)-cyanide metabolites under biomimetic conditions. J Inorg Biochem. 2001;85:67–76. doi: 10.1016/S0162-0134(00)00224-5. - DOI - PubMed
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Figure 4
Figure 4
THP-1 cells grown on gold foils showed significant decreased expression of lymphotoxin B (LTB) protein in cell culture supernatants compared with control cells after 4 days (n = 3, p 

Figure 5

THP-1 cells grown on gold…

Figure 5

THP-1 cells grown on gold foils showed significant decreased expression of fatty acid…

Figure 5
THP-1 cells grown on gold foils showed significant decreased expression of fatty acid desaturase 1 (FADS1) protein in cell culture supernatants compared with control cells after 4 days (n = 3, p 
Similar articles
References
    1. Burmester GR. Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update. Z Rheumatol. 2001;60:167–173. doi: 10.1007/s003930170065. - DOI - PubMed
    1. Simon LS, Yocum D. New and future drug therapies for rheumatoid arthritis. Rheumatol (Oxford) 2000;39(Suppl 1):36–42. doi: 10.1093/oxfordjournals.rheumatology.a031493. - DOI - PubMed
    1. Simon LS. DMARDs in the treatment of rheumatoid arthritis: current agents and future developments. Int J Clin Pract. 2000;54:243–249. - PubMed
    1. Jaeger GT, Larsen S, Soli N, Moe L. Two years follow-up study of the pain-relieving effect of gold bead implantation in dogs with hip-joint arthritis. Acta Vet Scand. 2007;49:9. doi: 10.1186/1751-0147-49-9. - DOI - PMC - PubMed
    1. Canumalla AJ, Al-Zamil N, Phillips M, Isab AA, Shaw CF 3rd. Redox and ligand exchange reactions of potential gold(I) and gold(III)-cyanide metabolites under biomimetic conditions. J Inorg Biochem. 2001;85:67–76. doi: 10.1016/S0162-0134(00)00224-5. - DOI - PubMed
Show all 59 references
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 5
Figure 5
THP-1 cells grown on gold foils showed significant decreased expression of fatty acid desaturase 1 (FADS1) protein in cell culture supernatants compared with control cells after 4 days (n = 3, p 

References

    1. Burmester GR. Molecular mechanisms of action of gold in treatment of rheumatoid arthritis--an update. Z Rheumatol. 2001;60:167–173. doi: 10.1007/s003930170065.
    1. Simon LS, Yocum D. New and future drug therapies for rheumatoid arthritis. Rheumatol (Oxford) 2000;39(Suppl 1):36–42. doi: 10.1093/oxfordjournals.rheumatology.a031493.
    1. Simon LS. DMARDs in the treatment of rheumatoid arthritis: current agents and future developments. Int J Clin Pract. 2000;54:243–249.
    1. Jaeger GT, Larsen S, Soli N, Moe L. Two years follow-up study of the pain-relieving effect of gold bead implantation in dogs with hip-joint arthritis. Acta Vet Scand. 2007;49:9. doi: 10.1186/1751-0147-49-9.
    1. Canumalla AJ, Al-Zamil N, Phillips M, Isab AA, Shaw CF 3rd. Redox and ligand exchange reactions of potential gold(I) and gold(III)-cyanide metabolites under biomimetic conditions. J Inorg Biochem. 2001;85:67–76. doi: 10.1016/S0162-0134(00)00224-5.
    1. Bondeson J, Sundler R. Auranofin inhibits the induction of interleukin 1 beta and tumor necrosis factor alpha mRNA in macrophages. Biochem Pharmacol. 1995;50:1753–1759. doi: 10.1016/0006-2952(95)02030-6.
    1. Yanni G, Nabil M, Farahat MR, Poston RN, Panayi GS. Intramuscular gold decreases cytokine expression and macrophage numbers in the rheumatoid synovial membrane. Ann Rheum Dis. 1994;53:315–322. doi: 10.1136/ard.53.5.315.
    1. Jaeger GT, Larsen S, Soli N, Moe L. Double-blind, placebo-controlled trial of the pain-relieving effects of the implantation of gold beads into dogs with hip dysplasia. Vet Rec. 2006;158:722–726. doi: 10.1136/vr.158.21.722.
    1. Mukherjee P, Bhattacharya R, Wang P, Wang L, Basu S, Nagy JA, Atala A, Mukhopadhyay D, Soker S. Antiangiogenic properties of gold nanoparticles. Clin Cancer Res. 2005;11:3530–3534. doi: 10.1158/1078-0432.CCR-04-2482.
    1. Jin H, Hong B, Kakar SS, Kang KA. Tumor-specific nano-entities for optical detection and hyperthermic treatment of breast cancer. Adv Exp Med Biol. 2008;614:275–284. doi: 10.1007/978-0-387-74911-2_31.
    1. Persellin RH, Ziff M. The effect of gold salt on lysosomal enzymes of the peritoneal macrophage. Arthritis Rheum. 1966;9:57–65. doi: 10.1002/art.1780090107.
    1. Traber KE, Okamoto H, Kurono C, Baba M, Saliou C, Soji T, Packer L, Okamoto T. Anti-rheumatic compound aurothioglucose inhibits tumor necrosis factor-alpha-induced HIV-1 replication in latently infected OM10.1 and Ach2 cells. Int Immunol. 1999;11:143–150. doi: 10.1093/intimm/11.2.143.
    1. Danscher G. In vivo liberation of gold ions from gold implants. Autometallographic tracing of gold in cells adjacent to metallic gold. Histochem Cell Biol. 2002;117:447–452. doi: 10.1007/s00418-002-0400-8.
    1. Larsen A, Stoltenberg M, Danscher G. In vitro liberation of charged gold atoms: autometallographic tracing of gold ions released by macrophages grown on metallic gold surfaces. Histochem Cell Biol. 2007;128:1–6. doi: 10.1007/s00418-007-0295-5.
    1. Szekanecz Z, Koch AE. Macrophages and their products in rheumatoid arthritis. Curr Opin Rheumatol. 2007;19:289–295. doi: 10.1097/BOR.0b013e32805e87ae.
    1. Okamoto H, Hoshi D, Kiire A, Yamanaka H, Kamatani N. Molecular targets of rheumatoid arthritis. Inflamm Allergy Drug Targets. 2008;7:53–66. doi: 10.2174/187152808784165199.
    1. Danscher G, Stoltenberg M. Silver enhancement of quantum dots resulting from (1) metabolism of toxic metals in animals and humans, (2) in vivo, in vitro and immersion created zinc-sulphur/zinc-selenium nanocrystals, (3) metal ions liberated from metal implants and particles. Prog Histochem Cytochem. 2006;41:57–139. doi: 10.1016/j.proghi.2006.06.001.
    1. Larsen A, Kolind K, Pedersen DS, Doering P, Pedersen MO, Danscher G, Penkowa M, Stoltenberg M. Gold ions bio-released from metallic gold particles reduce inflammation and apoptosis and increase the regenerative responses in focal brain injury. Histochem Cell Biol. 2008;130:681–692. doi: 10.1007/s00418-008-0448-1.
    1. Zdolsek JM, Olsson GM, Brunk UT. Photooxidative damage to lysosomes of cultured macrophages by acridine orange. Photochem Photobiol. 1990;51:67–76.
    1. Brunk UT, Dalen H, Roberg K, Hellquist HB. Photo-oxidative disruption of lysosomal membranes causes apoptosis of cultured human fibroblasts. Free Radic Biol Med. 1997;23:616–626. doi: 10.1016/S0891-5849(97)00007-5.
    1. Li W, Yuan X, Nordgren G, Dalen H, Dubowchik GM, Firestone RA, Brunk UT. Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett. 2000;470:35–39. doi: 10.1016/S0014-5793(00)01286-2.
    1. Helliwell PS, Taylor WJ. Treatment of psoriatic arthritis and rheumatoid arthritis with disease modifying drugs – comparison of drugs and adverse reactions. J Rheumatol. 2008;35:472–476.
    1. Danscher G, Larsen A. Effects of dissolucytotic gold ions on recovering brain lesions. Histochem Cell Biol. 2010;133:367–373. doi: 10.1007/s00418-010-0681-2.
    1. Pedersen MO, Larsen A, Stoltenberg M, Penkowa M. Bio-released gold ions modulate expression of neuroprotective and hematopoietic factors after brain injury. Brain Res. 2010;1307:1–13.
    1. Pedersen MO, Larsen A, Pedersen DS, Stoltenberg M, Penkowa M. Metallic gold reduces TNFalpha expression, oxidative DNA damage and pro-apoptotic signals after experimental brain injury. Brain Res. 2009;1271:103–113.
    1. Pedersen MO, Larsen A, Pedersen DS, Stoltenberg M, Penkova M. Metallic gold treatment reduces proliferation of inflammatory cells, increases expression of VEGF and FGF, and stimulates cell proliferation in the subventricular zone following experimental traumatic brain injury. Histol Histopathol. 2009;24:573–586.
    1. Kinne RW, Stuhlmuller B, Burmester GR. Cells of the synovium in rheumatoid arthritis. Macrophages. Arthritis Res Ther. 2007;9:224. doi: 10.1186/ar2333.
    1. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244–279. doi: 10.1016/j.pharmthera.2007.10.001.
    1. Mulherin D, Fitzgerald O, Bresnihan B. Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum. 1996;39:115–124. doi: 10.1002/art.1780390116.
    1. Singh JA, Pando JA, Tomaszewski J, Schumacher HR. Quantitative analysis of immunohistologic features of very early rheumatoid synovitis in disease modifying antirheumatic drug- and corticosteroid-naive patients. J Rheumatol. 2004;31:1281–1285.
    1. Vernon-Roberts B, Dore JL, Jessop JD, Henderson WJ. Selective concentration and localization of gold in macrophages of synovial and other tissues during and after chrysotherapy in rheumatoid patients. Ann Rheum Dis. 1976;35:477–486. doi: 10.1136/ard.35.6.477.
    1. Zetterstrom CK, Jiang W, Wahamaa H, Ostberg T, Aveberger AC, Schierbeck H, Lotze MT, Andersson U, Pisetsky DS, Erlandsson Harris H. Pivotal advance: inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate. J Leukoc Biol. 2008;83:31–38.
    1. Remouchamps C, Boutaffala L, Ganeff C, Dejardin E. Biology and signal transduction pathways of the Lymphotoxin-alphabeta/LTbetaR system. Cytokine Growth Factor Rev. 2011;22:301–310. doi: 10.1016/j.cytogfr.2011.11.007.
    1. O’Rourke KP, O’Donoghue G, Adams C, Mulcahy H, Molloy C, Silke C, Molloy M, Shanahan F, O’Gara F. High levels of Lymphotoxin-Beta (LT-Beta) gene expression in rheumatoid arthritis synovium: clinical and cytokine correlations. Rheumatol Int. 2008;28:979–986. doi: 10.1007/s00296-008-0574-z.
    1. Tureyen K, Brooks N, Bowen K, Svaren J, Vemuganti R. Transcription factor early growth response-1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia. J Neurochem. 2008;105:1313–1324. doi: 10.1111/j.1471-4159.2008.05233.x.
    1. Lohoff M, Giaisi M, Kohler R, Casper B, Krammer PH, Li-Weber M. Early growth response protein-1 (Egr-1) is preferentially expressed in T helper type 2 (Th2) cells and is involved in acute transcription of the Th2 cytokine interleukin-4. J Biol Chem. 2010;285:1643–1652. doi: 10.1074/jbc.M109.011585.
    1. Fahmi H. mPGES-1 as a novel target for arthritis. Curr Opin Rheumatol. 2004;16:623–627. doi: 10.1097/01.bor.0000129664.81052.8e.
    1. Martinelli N, Girelli D, Malerba G, Guarini P, Illig T, Trabetti E, Sandri M, Friso S, Pizzolo F, Schaeffer L. et al.FADS genotypes and desaturase activity estimated by the ratio of arachidonic acid to linoleic acid are associated with inflammation and coronary artery disease. Am J Clin Nutr. 2008;88:941–949.
    1. Joyce-Shaikh B, Bigler ME, Chao CC, Murphy EE, Blumenschein WM, Adamopoulos IE, Heyworth PG, Antonenko S, Bowman EP, McClanahan TK. et al.Myeloid DAP12-associating lectin (MDL)-1 regulates synovial inflammation and bone erosion associated with autoimmune arthritis. J Exp Med. 2010;207:579–589. doi: 10.1084/jem.20090516.
    1. Zhang H, Gao G, Clayburne G, Schumacher HR. Elimination of rheumatoid synovium in situ using a Fas ligand ‘gene scalpel’. Arthritis Res Ther. 2005;7:R1235–R1243. doi: 10.1186/ar1811.
    1. Grandaunet B, Syversen SW, Hoff M, Sundan A, Haugeberg G, van Der Heijde D, Kvien TK, Standal T. Association between high plasma levels of hepatocyte growth factor and progression of radiographic damage in the joints of patients with rheumatoid arthritis. Arthritis Rheum. 2011;63:662–669. doi: 10.1002/art.30163.
    1. Maruotti N, Cantatore FP, Crivellato E, Vacca A, Ribatti D. Angiogenesis in rheumatoid arthritis. Histol Histopathol. 2006;21:557–566.
    1. Yukioka K, Inaba M, Furumitsu Y, Yukioka M, Nishino T, Goto H, Nishizawa Y, Morii H. Levels of hepatocyte growth factor in synovial fluid and serum of patients with rheumatoid arthritis and release of hepatocyte growth factor by rheumatoid synovial fluid cells. J Rheumatol. 1994;21:2184–2189.
    1. Sakurai D, Tsuchiya N, Yamaguchi A, Okaji Y, Tsuno NH, Kobata T, Takahashi K, Tokunaga K. Crucial role of inhibitor of DNA binding/differentiation in the vascular endothelial growth factor-induced activation and angiogenic processes of human endothelial cells. J Immunol. 2004;173:5801–5809.
    1. Sakurai D, Yamaguchi A, Tsuchiya N, Yamamoto K, Tokunaga K. Expression of ID family genes in the synovia from patients with rheumatoid arthritis. Biochem Biophys Res Commun. 2001;284:436–442. doi: 10.1006/bbrc.2001.4974.
    1. Midwood K, Sacre S, Piccinini AM, Inglis J, Trebaul A, Chan E, Drexler S, Sofat N, Kashiwagi M, Orend G. et al.Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med. 2009;15:774–780. doi: 10.1038/nm.1987.
    1. Ruhmann M, Piccinini AM, Kong PL, Midwood KS. Endogenous activation of adaptive immunity: Tenascin-C drives IL-17 synthesis in arthritic joint disease. Arthritis Rheum. 2012;64(7):2179–2190. doi: 10.1002/art.34401.
    1. Sofat N, Robertson SD, Hermansson M, Jones J, Mitchell P, Wait R. Tenascin-C fragments are endogenous inducers of cartilage matrix degradation. Rheumatol Int. 2011;32(9):2809–2817.
    1. Goh FG, Piccinini AM, Krausgruber T, Udalova IA, Midwood KS. Transcriptional regulation of the endogenous danger signal tenascin-C: a novel autocrine loop in inflammation. J Immunol. 2010;184:2655–2662. doi: 10.4049/jimmunol.0903359.
    1. Burrage PS, Mix KS, Brinckerhoff CE. Matrix metalloproteinases: role in arthritis. Front Biosci. 2006;11:529–543. doi: 10.2741/1817.
    1. Wernicke D, Seyfert C, Gromnica-Ihle E, Stiehl P. The expression of collagenase 3 (MMP-13) mRNA in the synovial tissue is associated with histopathologic type II synovitis in rheumatoid arthritis. Autoimmunity. 2006;39:307–313. doi: 10.1080/08916930600807709.
    1. Migita K, Miyashita T, Ishibashi H, Maeda Y, Nakamura M, Yatsuhashi H, Ida H, Kawakami A, Aoyagi T, Kawabe Y, Eguchi K. Suppressive effect of leflunomide metabolite (A77 1726) on metalloproteinase production in IL-1beta stimulated rheumatoid synovial fibroblasts. Clin Exp Immunol. 2004;137:612–616. doi: 10.1111/j.1365-2249.2004.02555.x.
    1. Migita K, Miyashita T, Maeda Y, Aoyagi T, Kawabe Y, Nakamura M, Yatsuhashi H, Ishibashi H, Eguchi K. FK506 suppresses the stimulation of matrix metalloproteinase 13 synthesis by interleukin-1beta in rheumatoid synovial fibroblasts. Immunol Lett. 2005;98:194–199. doi: 10.1016/j.imlet.2004.11.014.
    1. Boyer JF, Balard P, Authier H, Faucon B, Bernad J, Mazieres B, Davignon JL, Cantagrel A, Pipy B, Constantin A. Tumor necrosis factor alpha and adalimumab differentially regulate CD36 expression in human monocytes. Arthritis Res Ther. 2007;9:R22. doi: 10.1186/ar2133.
    1. Wansa KD, Muscat GE. TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. J Mol Endocrinol. 2005;34:835–848. doi: 10.1677/jme.1.01739.
    1. De Silva S, Han S, Zhang X, Huston DP, Winoto A, Zheng B. Reduction of the incidence and severity of collagen-induced arthritis by constitutive Nur77 expression in the T cell lineage. Arthritis Rheum. 2005;52:333–338. doi: 10.1002/art.20736.
    1. Choy E. Understanding the dynamics: pathways involved in the pathogenesis of rheumatoid arthritis. Rheumatol (Oxford) 2012;51(Suppl 5):v3–11. doi: 10.1093/rheumatology/kes113.
    1. Vamnes JS, Gjerdet NR, Morken T, Moe G, Matre R. In vitro lymphocyte reactivity to gold compounds in the diagnosis of contact hypersensitivity. Contact Dermatitis. 1999;41:156–160. doi: 10.1111/j.1600-0536.1999.tb06108.x.
    1. Christiansen J, Farm G, Eid-Forest R, Anderson C, Cederbrant K, Hultman P. Interferon-gamma secreted from peripheral blood mononuclear cells as a possible diagnostic marker for allergic contact dermatitis to gold. Contact Dermatitis. 2006;55:101–112. doi: 10.1111/j.1600-0536.2006.00908.x.

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