Skip to main content

Advertisement

SpringerLink
Log in

Induced interleukin-8 expression in gliomas by tumor-associated macrophages

  • Laboratory Investigation - Human/Animal Tissue
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

The tumor microenvironment affects tumor initiation, progression, and metastasis. However, it is still not clear how stromal cells interact with the tumor cells. By using a cytokine array immunoblot assay, we showed that interleukin (IL)-8, IL-6, and RANTES (regulated upon activation normal T-cell expressed and secreted) proteins were up-regulated in GBM8401 glioma cells after coculture with human THP-1-derived macrophages. IL-8 is a chemokine with leukocyte chemotactic, tumorigenic, and proangiogenic properties. To evaluate the correlation of IL-8 expression with tumor-associated macrophages and angiogenesis, 43 glioma specimens were studied. The results showed that the IL-8 mRNA expression and microvessel count in glioma surgical specimens correlated positively with the density of tumor-associated macrophages. We further showed that IL-8 mRNA expression in GBM8401 cells increased dramatically, by 28–210-fold, after being cocultured with macrophages. This increase could also be induced by macrophage-conditioned medium, tumor necrosis factor-α, IL-1α, and IL-1β, and could be suppressed by anti-inflammatory agents including pyrrolidine dithiocarbamate, pentoxifylline, or dexamethasone. These findings imply that macrophage infiltration may be the common feature shared by cancer and inflammation, and macrophages could play a role in promoting glioma growth and angiogenesis by inducing IL-8 expression in glioma cells via inflammatory stimuli or the nuclear factor kappa B pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545. doi:10.1016/S0140-6736(00)04046-0

    Article  PubMed  CAS  Google Scholar 

  2. Balkwill F, Charles KA, Mantovani A (2005) Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7:211–217. doi:10.1016/j.ccr.2005.02.013

    Article  PubMed  CAS  Google Scholar 

  3. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867. doi:10.1038/nature01322

    Article  PubMed  CAS  Google Scholar 

  4. Polverini PJ (1997) Role of the macrophage in angiogenesis-dependent diseases. EXS 79:11–28

    PubMed  CAS  Google Scholar 

  5. Mantovani A, Sica A, Sozzani S et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686. doi:10.1016/j.it.2004.09.015

    Article  PubMed  CAS  Google Scholar 

  6. Kimura YN, Watari K, Fotovati A et al (2007) Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis. Cancer Sci 98:2009–2018. doi:10.1111/j.1349-7006.2007.00633.x

    Article  PubMed  CAS  Google Scholar 

  7. Allavena P, Sica A, Solinas G et al (2008) The inflammatory micro-environment in tumor progression: the role of tumor-associated macrophages. Crit Rev Oncol Hematol 66:1–9. doi:10.1016/j.critrevonc.2007.07.004

    Article  PubMed  Google Scholar 

  8. Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934

    PubMed  CAS  Google Scholar 

  9. Friesel RE, Maciag T (1995) Molecular mechanisms of angiogenesis: fibroblast growth factor signal transduction. FASEB J 9:919–925

    PubMed  CAS  Google Scholar 

  10. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364. doi:10.1016/S0092-8674(00)80108-7

    Article  PubMed  CAS  Google Scholar 

  11. Nagy JA, Brown LF, Senger DR et al (1989) Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. Biochim Biophys Acta 948:305–326

    PubMed  CAS  Google Scholar 

  12. Connolly DT, Stoddard BL, Harakas NK et al (1987) Human fibroblast-derived growth factor is a mitogen and chemoattractant for endothelial cells. Biochem Biophys Res Commun 144:705–712. doi:10.1016/S0006-291X(87)80022-0

    Article  PubMed  CAS  Google Scholar 

  13. Fukumura D, Xavier R, Sugiura T et al (1998) Tumor induction of VEGF promoter activity in stromal cells. Cell 94:715–725. doi:10.1016/S0092-8674(00)81731-6

    Article  PubMed  CAS  Google Scholar 

  14. Hussain SF, Yang D, Suki D et al (2006) The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol 8:261–279. doi:10.1215/15228517-2006-008

    Article  PubMed  CAS  Google Scholar 

  15. Badie B, Schartner J (2001) Role of microglia in glioma biology. Microsc Res Tech 54:106–113. doi:10.1002/jemt.1125

    Article  PubMed  CAS  Google Scholar 

  16. Brat DJ, Bellail AC, Van Meir EG (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 7:122–133. doi:10.1215/S1152851704001061

    Article  PubMed  CAS  Google Scholar 

  17. Smith DR, Polverini PJ, Kunkel SL et al (1994) Inhibition of interleukin-8 attenuates angiogenesis in bronchogenic carcinoma. J Exp Med 179:1409–1415. doi:10.1084/jem.179.5.1409

    Article  PubMed  CAS  Google Scholar 

  18. Singh RK, Gutman M, Radinsky R et al (1994) Expression of interleukin 8 correlates with the metastatic potential of human melanoma cells in nude mice. Cancer Res 54:3242–3247

    PubMed  CAS  Google Scholar 

  19. Inoue K, Slaton JW, Kim SJ et al (2000) Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer. Cancer Res 60:2290–2299

    PubMed  CAS  Google Scholar 

  20. Schadendorf D, Moller A, Algermissen B et al (1993) IL-8 produced by human malignant melanoma cells in vitro is an essential autocrine growth factor. J Immunol 151:2667–2675

    PubMed  CAS  Google Scholar 

  21. Yamanaka R, Tanaka R, Yoshida S et al (1995) Growth inhibition of human glioma cells modulated by retrovirus gene transfection with antisense IL-8. J Neurooncol 25:59–65. doi:10.1007/BF01054723

    Article  PubMed  CAS  Google Scholar 

  22. Brew R, Erikson JS, West DC et al (2000) Interleukin-8 as an autocrine growth factor for human colon carcinoma cells in vitro. Cytokine 12:78–85. doi:10.1006/cyto.1999.0518

    Article  PubMed  CAS  Google Scholar 

  23. Miyamoto M, Shimizu Y, Okada K et al (1998) Effect of interleukin-8 on production of tumor-associated substances and autocrine growth of human liver and pancreatic cancer cells. Cancer Immunol Immunother 47:47–57. doi:10.1007/s002620050503

    Article  PubMed  CAS  Google Scholar 

  24. Yao PL, Lin YC, Wang CH et al (2005) Autocrine and paracrine regulation of interleukin-8 expression in lung cancer cells. Am J Respir Cell Mol Biol 32:540–547. doi:10.1165/rcmb.2004-0223OC

    Article  PubMed  CAS  Google Scholar 

  25. Norgauer J, Metzner B, Schraufstatter I (1996) Expression and growth-promoting function of the IL-8 receptor beta in human melanoma cells. J Immunol 156:1132–1137

    PubMed  CAS  Google Scholar 

  26. Li A, Dubey S, Varney ML et al (2003) IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170:3369–3376

    PubMed  CAS  Google Scholar 

  27. Kasahara T, Mukaida N, Yamashita K et al (1991) IL-1 and TNF-alpha induction of IL-8 and monocyte chemotactic and activating factor (MCAF) mRNA expression in a human astrocytoma cell line. Immunology 74:60–67

    PubMed  CAS  Google Scholar 

  28. Wakabayashi Y, Shono T, Isono M et al (1995) Dual pathways of tubular morphogenesis of vascular endothelial cells by human glioma cells: vascular endothelial growth factor/basic fibroblast growth factor and interleukin-8. Jpn J Cancer Res 86:1189–1197

    PubMed  CAS  Google Scholar 

  29. Tsuchiya S, Yamabe M, Yamaguchi Y et al (1980) Establishment and characterization of a human acute monocytic leukemia cell line (THP-1). Int J Cancer 26:171–176. doi:10.1002/ijc.2910260208

    Article  PubMed  CAS  Google Scholar 

  30. Auwerx J (1991) The human leukemia cell line, THP-1: a multifaceted model for the study of monocyte–macrophage differentiation. Experientia 47:22–31. doi:10.1007/BF02041244

    Article  PubMed  CAS  Google Scholar 

  31. Yuan A, Yang PC, Yu CJ et al (2000) Interleukin-8 messenger ribonucleic acid expression correlates with tumor progression, tumor angiogenesis, patient survival, and timing of relapse in non-small-cell lung cancer. Am J Respir Crit Care Med 162:1957–1963

    PubMed  CAS  Google Scholar 

  32. Mori N, Oishi K, Sar B et al (1999) Essential role of transcription factor nuclear factor-kappa B in regulation of interleukin-8 gene expression by nitrite reductase from Pseudomonas aeruginosa in respiratory epithelial cells. Infect Immun 67:3872–3878

    PubMed  CAS  Google Scholar 

  33. Jain VK, Magrath IT (1991) A chemiluminescent assay for quantitation of beta-galactosidase in the femtogram range: application to quantitation of beta-galactosidase in lacZ-transfected cells. Anal Biochem 199:119–124. doi:10.1016/0003-2697(91)90278-2

    Article  PubMed  CAS  Google Scholar 

  34. Leek RD, Hunt NC, Landers RJ et al (2000) Macrophage infiltration is associated with VEGF and EGFR expression in breast cancer. J Pathol 190:430–436. doi:10.1002/(SICI)1096-9896(200003)190:4<430::AID-PATH538>3.0.CO;2-6

    Article  PubMed  CAS  Google Scholar 

  35. Chen JJ, Yao PL, Yuan A et al (2003) Up-regulation of tumor interleukin-8 expression by infiltrating macrophages: its correlation with tumor angiogenesis and patient survival in non-small cell lung cancer. Clin Cancer Res 9:729–737

    PubMed  CAS  Google Scholar 

  36. Hoffmann E, Dittrich-Breiholz O, Holtmann H et al (2002) Multiple control of interleukin-8 gene expression. J Leukoc Biol 72:847–855

    PubMed  CAS  Google Scholar 

  37. Holland EC (2000) Glioblastoma multiforme: the terminator. Proc Natl Acad Sci USA 97:6242–6244. doi:10.1073/pnas.97.12.6242

    Article  PubMed  CAS  Google Scholar 

  38. Tsai JC, Goldman CK, Gillespie GY (1995) Vascular endothelial growth factor in human glioma cell lines: induced secretion by EGF, PDGF-BB, and bFGF. J Neurosurg 82:864–873

    PubMed  CAS  Google Scholar 

  39. Hashimoto I, Kodama J, Seki N et al (2000) Macrophage infiltration and angiogenesis in endometrial cancer. Anticancer Res 20:4853–4856

    PubMed  CAS  Google Scholar 

  40. Leek RD, Lewis CE, Whitehouse R et al (1996) Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res 56:4625–4629

    PubMed  CAS  Google Scholar 

  41. Fukuyama T, Ichiki Y, Yamada S et al (2007) Cytokine production of lung cancer cell lines: Correlation between their production and the inflammatory/immunological responses both in vivo and in vitro. Cancer Sci 98:1048–1054. doi:10.1111/j.1349-7006.2007.00507.x

    Article  PubMed  CAS  Google Scholar 

  42. Kreutzberg GW (1996) Microglia: a sensor for pathological events in the CNS. Trends Neurosci 19:312–318. doi:10.1016/0166-2236(96)10049-7

    Article  PubMed  CAS  Google Scholar 

  43. Flugel A, Bradl M, Kreutzberg GW et al (2001) Transformation of donor-derived bone marrow precursors into host microglia during autoimmune CNS inflammation and during the retrograde response to axotomy. J Neurosci Res 66:74–82. doi:10.1002/jnr.1198

    Article  PubMed  CAS  Google Scholar 

  44. Frei K, Piani D, Malipiero UV et al (1992) Granulocyte-macrophage colony-stimulating factor (GM-CSF) production by glioblastoma cells. Despite the presence of inducing signals GM-CSF is not expressed in vivo. J Immunol 148:3140–3146

    PubMed  CAS  Google Scholar 

  45. Schall TJ, Bacon K, Toy KJ et al (1990) Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 347:669–671. doi:10.1038/347669a0

    Article  PubMed  CAS  Google Scholar 

  46. Cohen T, Nahari D, Cerem LW et al (1996) Interleukin-6 induces the expression of vascular endothelial growth factor. J Biol Chem 271:736–741. doi:10.1074/jbc.271.2.736

    Article  PubMed  CAS  Google Scholar 

  47. Baggiolini M, Walz A, Kunkel SL (1989) Neutrophil-activating peptide-1/interleukin-8, a novel cytokine that activates neutrophils. J Clin Invest 84:1045–1049. doi:10.1172/JCI114265

    Article  PubMed  CAS  Google Scholar 

  48. Ueda T, Shimada E, Urakawa T (1994) Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. J Gastroenterol 29:423–429. doi:10.1007/BF02361238

    Article  PubMed  CAS  Google Scholar 

  49. Desbaillets I, Diserens AC, Tribolet N et al (1997) Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. J Exp Med 186:1201–1212. doi:10.1084/jem.186.8.1201

    Article  PubMed  CAS  Google Scholar 

  50. Jouanneau E (2008) Angiogenesis and gliomas: current issues and development of surrogate markers. Neurosurgery 62:31–50

    Article  PubMed  Google Scholar 

  51. Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20:4368–4380. doi:10.1200/JCO.2002.10.088

    Article  PubMed  CAS  Google Scholar 

  52. Roberts AB, Sporn MB, Assoian RK et al (1986) Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 83:4167–4171. doi:10.1073/pnas.83.12.4167

    Article  PubMed  CAS  Google Scholar 

  53. Mizukami Y, Jo WS, Duerr EM et al (2005) Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat Med 11:992–997

    PubMed  CAS  Google Scholar 

  54. Ferrari G, Pintucci G, Seghezzi G et al (2006) VEGF, a prosurvival factor, acts in concert with TGF-beta1 to induce endothelial cell apoptosis. Proc Natl Acad Sci USA 103:17260–17265. doi:10.1073/pnas.0605556103

    Article  PubMed  CAS  Google Scholar 

  55. White ES, Strom SR, Wys NL et al (2001) Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity. J Immunol 166:7549–7555

    PubMed  CAS  Google Scholar 

  56. Lin SL, Chen YM, Chien CT et al (2002) Pentoxifylline attenuated the renal disease progression in rats with remnant kidney. J Am Soc Nephrol 13:2916–2929. doi:10.1097/01.ASN.0000034909.10994.8A

    Article  PubMed  CAS  Google Scholar 

  57. Chen YM, Chiang WC, Lin SL et al (2004) Dual regulation of tumor necrosis factor-alpha-induced CCL2/monocyte chemoattractant protein-1 expression in vascular smooth muscle cells by nuclear factor-kappa B and activator protein-1: modulation by type III phosphodiesterase inhibition. J Pharmacol Exp Ther 309:978–986. doi:10.1124/jpet.103.062620

    Article  PubMed  CAS  Google Scholar 

  58. Brennan P, O’Neill LA (1996) 2-mercaptoethanol restores the ability of nuclear factor kappa B (NF kappa B) to bind DNA in nuclear extracts from interleukin 1-treated cells incubated with pyrollidine dithiocarbamate (PDTC). Evidence for oxidation of glutathione in the mechanism of inhibition of NF kappa B by PDTC. Biochem J 320:975–981

    PubMed  Google Scholar 

  59. Schreck R, Meier B, Mannel DN et al (1992) Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. J Exp Med 175:1181–1194. doi:10.1084/jem.175.5.1181

    Article  PubMed  CAS  Google Scholar 

  60. Rahman I, MacNee W (1998) Role of transcription factors in inflammatory lung diseases. Thorax 53:601–612

    Article  PubMed  CAS  Google Scholar 

  61. Meng L, Zhou J, Sasano H et al (2001) Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferators-activated receptor gamma: mechanism of desmoplastic reaction. Cancer Res 61:2250–2255

    PubMed  CAS  Google Scholar 

  62. Mukaida N, Mahe Y, Matsushima K (1990) Cooperative interaction of nuclear factor-kappa B- and cis-regulatory enhancer binding protein-like factor binding elements in activating the interleukin-8 gene by pro-inflammatory cytokines. J Biol Chem 265:21128–21133

    PubMed  CAS  Google Scholar 

  63. Harant H, de Martin R, Andrew PJ et al (1996) Synergistic activation of interleukin-8 gene transcription by all-trans-retinoic acid and tumor necrosis factor-alpha involves the transcription factor NF-kappa B. J Biol Chem 271:26954–26961. doi:10.1074/jbc.271.43.26954

    Article  PubMed  CAS  Google Scholar 

  64. Szelenyi J (2001) Cytokines and the central nervous system. Brain Res Bull 54:329–338. doi:10.1016/S0361-9230(01)00428-2

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by Grant NSC 93-2314-B-002-243 from the National Science Council (Taipei, Taiwan) and Grant NTUH 94S136 from the National Taiwan University Hospital (Taipei, Taiwan).

Author information

Authors and Affiliations

  1. NTU Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan

    Tse-Ming Hong

  2. Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University College of Medicine, Taipei, Taiwan

    Lee-Jene Teng

  3. Department of Forensic Medicine and Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan

    Chia-Tung Shun

  4. Center for Optoelectronic Biomedicine, National Taiwan University College of Medicine, Taipei, Taiwan

    Mei-Chen Peng

  5. Department of Surgery, Division of Neurosurgery, National Taiwan University Hospital and Center for Optoelectronic Biomedicine, National Taiwan University College of Medicine, Room 822, 8th floor, Number 7 Chung-Shan South Road, Taipei, 10002, Taiwan

    Jui-Chang Tsai

Authors
  1. Tse-Ming Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lee-Jene Teng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chia-Tung Shun
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mei-Chen Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jui-Chang Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jui-Chang Tsai.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hong, TM., Teng, LJ., Shun, CT. et al. Induced interleukin-8 expression in gliomas by tumor-associated macrophages. J Neurooncol 93, 289–301 (2009). https://doi.org/10.1007/s11060-008-9786-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-008-9786-z

Keywords

Search

Navigation