Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1997 Dec 15;328(Pt 3):923–928. doi: 10.1042/bj3280923

Role of membrane-anchored heparin-binding epidermal growth factor-like growth factor and CD9 on macrophages.

N Ouchi 1, S Kihara 1, S Yamashita 1, S Higashiyama 1, T Nakagawa 1, I Shimomura 1, T Funahashi 1, K Kameda-Takemura 1, S Kawata 1, N Taniguchi 1, Y Matsuzawa 1
PMCID: PMC1219005  PMID: 9396739

Abstract

Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) is a potent mitogen for smooth-muscle cells (SMCs) belonging to the EGF family. We have previously determined that HB-EGF is expressed in macrophages and SMCs of human atherosclerotic lesions and that its membrane-anchored precursor, proHB-EGF, also has a juxtacrine mitogenic activity which is markedly enhanced by CD9, a surface marker of lymphohaemopoietic cells. Therefore, when both proHB-EGF and CD9 are expressed on macrophages, they may strongly promote the development of atherosclerosis. In the present study we have investigated the changes in proHB-EGF and CD9 in THP-1 cells during differentiation into macrophages and by the addition of oxidized low-density lipoproteins (OxLDL) and assessed juxtacrine growth activity of THP-1 macrophages for human aortic SMCs. HB-EGF and CD9 at both the mRNA and the protein level were up-regulated after differentiation into macrophages, and further expression of HB-EGF was induced by the addition of OxLDL or lysophosphatidylcholine. Juxtacrine induction by formalin-fixed growth was suppressed to control levels by an inhibitor of HB-EGF and was partially decreased by anti-CD9 antibodies. These results suggest that co-expression of proHB-EGF and CD9 on macrophages plays an important role in the development of atherosclerosis by a juxtacrine mechanism.

Full Text

The Full Text of this article is available as a PDF (309.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Auwerx J. H., Deeb S., Brunzell J. D., Peng R., Chait A. Transcriptional activation of the lipoprotein lipase and apolipoprotein E genes accompanies differentiation in some human macrophage-like cell lines. Biochemistry. 1988 Apr 19;27(8):2651–2655. doi: 10.1021/bi00408a003. [DOI] [PubMed] [Google Scholar]
  2. Banka C. L., Black A. S., Dyer C. A., Curtiss L. K. THP-1 cells form foam cells in response to coculture with lipoproteins but not platelets. J Lipid Res. 1991 Jan;32(1):35–43. [PubMed] [Google Scholar]
  3. Barendsen N., Mueller M., Chen B. Inhibition of TPA-induced monocytic differentiation in THP-1 human monocytic leukemic cells by staurosporine, a potent protein kinase C inhibitor. Leuk Res. 1990;14(5):467–474. doi: 10.1016/0145-2126(90)90034-7. [DOI] [PubMed] [Google Scholar]
  4. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  5. Endemann G., Stanton L. W., Madden K. S., Bryant C. M., White R. T., Protter A. A. CD36 is a receptor for oxidized low density lipoprotein. J Biol Chem. 1993 Jun 5;268(16):11811–11816. [PubMed] [Google Scholar]
  6. FOLCH J., LEES M., SLOANE STANLEY G. H. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957 May;226(1):497–509. [PubMed] [Google Scholar]
  7. Higashiyama S., Abraham J. A., Klagsbrun M. Heparin-binding EGF-like growth factor stimulation of smooth muscle cell migration: dependence on interactions with cell surface heparan sulfate. J Cell Biol. 1993 Aug;122(4):933–940. doi: 10.1083/jcb.122.4.933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Higashiyama S., Abraham J. A., Miller J., Fiddes J. C., Klagsbrun M. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science. 1991 Feb 22;251(4996):936–939. doi: 10.1126/science.1840698. [DOI] [PubMed] [Google Scholar]
  9. Higashiyama S., Iwamoto R., Goishi K., Raab G., Taniguchi N., Klagsbrun M., Mekada E. The membrane protein CD9/DRAP 27 potentiates the juxtacrine growth factor activity of the membrane-anchored heparin-binding EGF-like growth factor. J Cell Biol. 1995 Mar;128(5):929–938. doi: 10.1083/jcb.128.5.929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Higashiyama S., Lau K., Besner G. E., Abraham J. A., Klagsbrun M. Structure of heparin-binding EGF-like growth factor. Multiple forms, primary structure, and glycosylation of the mature protein. J Biol Chem. 1992 Mar 25;267(9):6205–6212. [PubMed] [Google Scholar]
  11. Iwamoto R., Higashiyama S., Mitamura T., Taniguchi N., Klagsbrun M., Mekada E. Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity. EMBO J. 1994 May 15;13(10):2322–2330. doi: 10.1002/j.1460-2075.1994.tb06516.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Iwamoto R., Senoh H., Okada Y., Uchida T., Mekada E. An antibody that inhibits the binding of diphtheria toxin to cells revealed the association of a 27-kDa membrane protein with the diphtheria toxin receptor. J Biol Chem. 1991 Oct 25;266(30):20463–20469. [PubMed] [Google Scholar]
  13. Kamido H., Matsuzawa Y., Tarui S. Lipid composition of platelets from patients with atherosclerosis: effect of purified eicosapentaenoic acid ethyl ester administration. Lipids. 1988 Oct;23(10):917–923. doi: 10.1007/BF02536337. [DOI] [PubMed] [Google Scholar]
  14. Kersey J. H., LeBien T. W., Abramson C. S., Newman R., Sutherland R., Greaves M. P-24: a human leukemia-associated and lymphohemopoietic progenitor cell surface structure identified with monoclonal antibody. J Exp Med. 1981 Mar 1;153(3):726–731. doi: 10.1084/jem.153.3.726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kodama T., Reddy P., Kishimoto C., Krieger M. Purification and characterization of a bovine acetyl low density lipoprotein receptor. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9238–9242. doi: 10.1073/pnas.85.23.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kosaka C., Masuda J., Shimokado K., Zen K., Yokota T., Sasaguri T., Ogata J. Interferon-gamma suppresses PDGF production from THP-1 cells and blood monocyte-derived macrophages. Atherosclerosis. 1992 Nov;97(1):75–87. doi: 10.1016/0021-9150(92)90053-j. [DOI] [PubMed] [Google Scholar]
  17. Kume N., Cybulsky M. I., Gimbrone M. A., Jr Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leukocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest. 1992 Sep;90(3):1138–1144. doi: 10.1172/JCI115932. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kume N., Gimbrone M. A., Jr Lysophosphatidylcholine transcriptionally induces growth factor gene expression in cultured human endothelial cells. J Clin Invest. 1994 Feb;93(2):907–911. doi: 10.1172/JCI117047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  20. Malden L. T., Chait A., Raines E. W., Ross R. The influence of oxidatively modified low density lipoproteins on expression of platelet-derived growth factor by human monocyte-derived macrophages. J Biol Chem. 1991 Jul 25;266(21):13901–13907. [PubMed] [Google Scholar]
  21. Menju M., Tajima S., Yamamoto A. Expression of the apolipoprotein E gene in a human macrophage-like cell line, THP-1. J Biochem. 1989 Sep;106(3):505–510. doi: 10.1093/oxfordjournals.jbchem.a122882. [DOI] [PubMed] [Google Scholar]
  22. Mitamura T., Iwamoto R., Umata T., Yomo T., Urabe I., Tsuneoka M., Mekada E. The 27-kD diphtheria toxin receptor-associated protein (DRAP27) from vero cells is the monkey homologue of human CD9 antigen: expression of DRAP27 elevates the number of diphtheria toxin receptors on toxin-sensitive cells. J Cell Biol. 1992 Sep;118(6):1389–1399. doi: 10.1083/jcb.118.6.1389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Miyagawa J., Higashiyama S., Kawata S., Inui Y., Tamura S., Yamamoto K., Nishida M., Nakamura T., Yamashita S., Matsuzawa Y. Localization of heparin-binding EGF-like growth factor in the smooth muscle cells and macrophages of human atherosclerotic plaques. J Clin Invest. 1995 Jan;95(1):404–411. doi: 10.1172/JCI117669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Moscatelli D. High and low affinity binding sites for basic fibroblast growth factor on cultured cells: absence of a role for low affinity binding in the stimulation of plasminogen activator production by bovine capillary endothelial cells. J Cell Physiol. 1987 Apr;131(1):123–130. doi: 10.1002/jcp.1041310118. [DOI] [PubMed] [Google Scholar]
  25. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  26. Nozaki S., Kubo M., Sudo H., Matsuzawa Y., Tarui S. The role of hepatic triglyceride lipase in the metabolism of intermediate-density lipoprotein--postheparin lipolytic activities determined by a sensitive, nonradioisotopic method in hyperlipidemic patients and normals. Metabolism. 1986 Jan;35(1):53–58. doi: 10.1016/0026-0495(86)90095-8. [DOI] [PubMed] [Google Scholar]
  27. Quinn M. T., Parthasarathy S., Steinberg D. Lysophosphatidylcholine: a chemotactic factor for human monocytes and its potential role in atherogenesis. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2805–2809. doi: 10.1073/pnas.85.8.2805. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ross R., Masuda J., Raines E. W., Gown A. M., Katsuda S., Sasahara M., Malden L. T., Masuko H., Sato H. Localization of PDGF-B protein in macrophages in all phases of atherogenesis. Science. 1990 May 25;248(4958):1009–1012. doi: 10.1126/science.2343305. [DOI] [PubMed] [Google Scholar]
  29. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993 Apr 29;362(6423):801–809. doi: 10.1038/362801a0. [DOI] [PubMed] [Google Scholar]
  30. Rouser G., Fkeischer S., Yamamoto A. Two dimensional then layer chromatographic separation of polar lipids and determination of phospholipids by phosphorus analysis of spots. Lipids. 1970 May;5(5):494–496. doi: 10.1007/BF02531316. [DOI] [PubMed] [Google Scholar]
  31. Sakai M., Miyazaki A., Hakamata H., Sasaki T., Yui S., Yamazaki M., Shichiri M., Horiuchi S. Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages. J Biol Chem. 1994 Dec 16;269(50):31430–31435. [PubMed] [Google Scholar]
  32. Shimokado K., Raines E. W., Madtes D. K., Barrett T. B., Benditt E. P., Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985 Nov;43(1):277–286. doi: 10.1016/0092-8674(85)90033-9. [DOI] [PubMed] [Google Scholar]
  33. Steinberg D., Parthasarathy S., Carew T. E., Khoo J. C., Witztum J. L. Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med. 1989 Apr 6;320(14):915–924. doi: 10.1056/NEJM198904063201407. [DOI] [PubMed] [Google Scholar]
  34. Thompson S. A., Higashiyama S., Wood K., Pollitt N. S., Damm D., McEnroe G., Garrick B., Ashton N., Lau K., Hancock N. Characterization of sequences within heparin-binding EGF-like growth factor that mediate interaction with heparin. J Biol Chem. 1994 Jan 28;269(4):2541–2549. [PubMed] [Google Scholar]
  35. Tsuchiya S., Kobayashi Y., Goto Y., Okumura H., Nakae S., Konno T., Tada K. Induction of maturation in cultured human monocytic leukemia cells by a phorbol diester. Cancer Res. 1982 Apr;42(4):1530–1536. [PubMed] [Google Scholar]
  36. Via D. P., Pons L., Dennison D. K., Fanslow A. E., Bernini F. Induction of acetyl-LDL receptor activity by phorbol ester in human monocyte cell line THP-1. J Lipid Res. 1989 Oct;30(10):1515–1524. [PubMed] [Google Scholar]
  37. Witztum J. L., Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest. 1991 Dec;88(6):1785–1792. doi: 10.1172/JCI115499. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES