Skip to main content
SpringerLink
Log in

TNF-alpha employs a protein-tyrosine phosphatase to inhibit activation of hepatocyte growth factor receptor and hepatocyte growth factor-induced endothelial cell proliferation

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

TNF-alpha impairs endothelial cell growth and angiogenesis. The anti-angiogenic effects of TNF-alpha have mainly been explained by its modulating vascular endothelial growth factor (VEGF)-specific angiogenic pathway. Hepatocyte growth factor (HGF) also promotes the growth of vascular endothelial cells and the development of new blood vessels through interaction with its specific receptor, c-met. However, it is little known whether TNF-alpha interacts with the HGF system or not. In this study, we examined the effect of TNF-alpha on HGF receptor function. In human umbilical venous endothelial cells (HUVEC), TNF-alpha acutely inhibited the phosphorylation and activation of c-met induced by HGF. The ability of TNF-alpha to inhibit HGF-induced c-met activity was impaired by sodium orthovanadate, suggesting that the inhibitory effect of TNF-alpha was mediated by a protein-tyrosine phosphatase. Treatment of HUVEC with TNF-alpha impairs the ability of HGF to activate MAPK and Akt, and this effect was blocked by SOV. HGF-induced c-met responses specifically associated with endothelial cell proliferation and mitogen-activated protein kinase activation were also inhibited by TNF-alpha, and these were reversed by sodium orthovanadate. HGF-induced SHP-1 (a cytoplasmic protein-tyrosine phosphatase) and pretreatment of HUVEC with TNF-alpha prior to HGF treatment resulted in substantial increase in the amount of SHP-1. These data suggest that TNF-alpha employs a protein-tyrosine phosphatase and may exert its anti-angiogenic function in part by modulating the HGF-specific angiogenic pathway in pathological settings.

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

Similar content being viewed by others

References

  1. Takeshita S, Zheng LP, Brogi E, Kearney M, Pu LQ, Bunting S, Ferrara N, Symes JF, Isner JM (1994) Therapeutic angiogenesis: a single intraarterial bonus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. J Clin Invest 93:662–670

    Article  PubMed  CAS  Google Scholar 

  2. Pearlman JD, Hibberd MG, Chuang ML, Harada K, Lopez JJ, Gladstone SR, Friedman M, Sellke FW, Simons M (1995) Magnetic resonance mapping demonstrates benefits of VEGF-induced myocardial angiogenesis. Nat Med 1:1085–1089

    Article  PubMed  CAS  Google Scholar 

  3. Banai S, Jaklitsch MT, Shou M, Lazarous DF, Scheinowitz M, Biro S, Epstein SE, Unger EF (1994) Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs. Circulation 89:2183–2189

    PubMed  CAS  Google Scholar 

  4. Harada K, Friedman M, Lopez JJ, Wang SY, Li J, Prasad PV, Pearlman JD, Edelman ER, Sellke FW, Simons M (1996) Vascular endothelial growth factor administration in chronic myocardial ischemia. Am J Physiol 270:H1791–H1802

    PubMed  CAS  Google Scholar 

  5. Stolpen AH, Guinan EC, Fiers W, Pober JS (1986) Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am J Pathol 123(1):16–24

    PubMed  CAS  Google Scholar 

  6. Sato N, Goto T, Haranaka K, Satomi N, Nariuchi H, Mano-Hirano Y, Sawasaki Y (1986) Actions of tumor necrosis factor on cultured vascular endothelial cells: morphologic modulation, growth inhibition, and cytotoxicity. J Nat Cancer Inst 76(6):1113–1121

    PubMed  CAS  Google Scholar 

  7. Patterson C, Perrella MA, Endege WO, Yoshizumi M, Lee MN, Haber E (1996) Downregulation of vascular endothelial growth factor receptors by tumor necrosis factor-α in cultured human vascular endothelial cells. J Clin Invest 98:490–496

    Article  PubMed  CAS  Google Scholar 

  8. Guo DQ, Wu LW, Dunbar JD, Ozes ON, Mayo LD, Kessler KM, Gustin JA, Baerwald MR, Jaffe EA, Warren RS, Donner DB (2000) Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. J Biol Chem 275:11216–11221

    Article  PubMed  CAS  Google Scholar 

  9. Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S (1997) Enhanced expression of hepatocyte growth factor/c-Met by myocardial ischemia and reperfusion in a rat model. Circulation 95:2552–2558

    PubMed  CAS  Google Scholar 

  10. Bussolino F, DiRenzo MF, Ziche M, Bocchietto E, Olivero M, Naidini L, Gaudino G, Tmagnone L, Coffer A, Comoglio PM (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641

    Article  PubMed  CAS  Google Scholar 

  11. Hayashi S, Morishita R, Higaki J, Aoki M, Motiguchi A, Kida I, Yoshiki S, Matsumoto K, Nakamura T, Kanada Y, Ogihara T (1996) Autocrine-paracrine effects of overexpression of hepatocyte growth factor gene on growth of endothelial cells. Biochem Biophys Res Commun 220:539–545

    Article  PubMed  CAS  Google Scholar 

  12. Morishita R, Nakamura S, Hayashi S, Taniyama Y, Motiguchi A, Nagano T, Taiji M, Noguchi H, Takeshita S, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1999) Therapeutic angiogenesis induced by human recombinant hepatocyte growth factor in rabbit hind limb ischemia model as cytokine supplement therapy. Hypertension 33:1379–1384

    PubMed  CAS  Google Scholar 

  13. Yo Y, Morishita R, Nakamura S, Tomita N, Yamamoto K, Moriguchi A, Matsumoto K, Nakamura T, Higaki J, Ogihara T (1998) Potential role of hepatocyte growth factor in the maintenance of renal structure: anti-apoptotic action of HGF on epithelial cells. Kidney Int 54:1392–1393

    Article  Google Scholar 

  14. Duan HF, Wu CT, Lu Y, Wang H, Liu HJ, Zhang QW, Jia XX, Lu ZZ, Wang LS (2004) Sphingosine kinase activation regulates hepatocyte growth factor induced migration of endothelial cells. Exp Cell Res 298:593–601

    Article  PubMed  CAS  Google Scholar 

  15. Frater-Schroder M, Risau W, Hallmann R, Gautschi P, Bohlen P (1987) Tumor necrosis factor type alpha, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Nat Acad Sci 84:5277–5281

    Article  PubMed  CAS  Google Scholar 

  16. Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N (1987) Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329:630–632

    Article  PubMed  CAS  Google Scholar 

  17. Spyridopoulos I, Sullivan AB, Kearney M, Isner JM, Losordo DW (1997) Estrogen-receptor-mediated inhibition of human endothelial cell apoptosis: estradiol as a survival factor. Circulation 95:1505–1514

    PubMed  CAS  Google Scholar 

  18. Sata M, Walsh K (1998) TNF α regulation of Fas ligand expression on the vascular endothelium modulates leukocyte extravasation. Nature Med 4:415–420

    Article  PubMed  CAS  Google Scholar 

  19. Taniyama Y, Morishita R, Aoki M, Nakagami H, Yamamoto K, Yamazaki K, Matsumoto K, Nakamura T, Kaneda Y, Ogihara T (2001) Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease. Gene Ther 8:181–189

    Article  PubMed  CAS  Google Scholar 

  20. Lei X, Buja LM (1996) Detection and localization of tumor necrosis factor-alpha in WHHL rabbit arteries. Atherosclerosis 125:81–89

    Article  PubMed  CAS  Google Scholar 

  21. Tanaka H, Swanson SI, Sukhova G, Schoen FI, Libby P (1995) Smooth muscle cells of the coronary arterial tunica media express tumor necrosis factor-α and proliferate during acute rejection of rabbit cardiac allografts. Am J Pathol 147:617–626

    PubMed  CAS  Google Scholar 

  22. Clausell N, de Lima VC, Molossi S, Liu P, Turley E, Gotlieb AI, Adelman AG, Rabinovitch M (1995) Expression of tumor necrosis factor alpha and accumulation of fibronectin in coronary artery restenotic lesion retrieved by atherectomy. Br Heart J 73:534–539

    Article  PubMed  CAS  Google Scholar 

  23. Tanaka H, Sukhova G, Schwartz D, Libby P (1996) Proliferating arterial smooth muscle cells after balloon injury express TNF-α but not interleukin-1 or basic fibroblast growth factor. Arterioscler Thromb Vasc Biol 16:12–18

    PubMed  CAS  Google Scholar 

  24. Sugano M, Tsuchida K, Makino N (2004) Intramuscular gene transfer of soluble TNF-alpha receptor 1 activates vascular endothelial growth factor receptor (KDR/flk-1) and accelerates angiogenesis in a rat model of hindlimb ischemia. Circulation 109:797–802

    Article  PubMed  CAS  Google Scholar 

  25. Sugano M, Tsuchida K, Makino N (2004) A protein tyrosine phosphatase inhibitor accelerates angiogenesis in a rat model of hindlimb ischemia. J Cardiovasc Pharmacol 44:460–465

    Article  PubMed  CAS  Google Scholar 

  26. Sugano M, Tsuchida K, Maeda T, Makino N (2007) SiRNA targeting SHP-1 accelerates angiogenesis in a rat model of hindlimb ischemia. Atherosclerosis 191:33–39

    Article  PubMed  CAS  Google Scholar 

  27. Nakagami H, Cui TX, Iwai M, Shiuchi T, Takeda-Matsubara Y, Wu L, Horiuchi M (2002) Tumor necrosis factor-alpha inhibits growth factor-mediated cell proliferation through SHP-1 activation in endothelial cells. Arterioscler Thromb Vasc Biol 22:238–242

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Human Biology, Department of Health Science, Oita University of Nursing and Health Science, 2944 Megusuno, Oita, 870-1201, Japan

    Masahiro Sugano, Yoshiko Iwasaki & Masako Abe

  2. Department of Molecular and Cellular Biology, Division of Molecular and Clinical Gerontology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu, 874-0838, Japan

    Toyoki Maeda, Keiko Tsuchida & Naoki Makino

Authors
  1. Masahiro Sugano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshiko Iwasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masako Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toyoki Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiko Tsuchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoki Makino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Masahiro Sugano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugano, M., Iwasaki, Y., Abe, M. et al. TNF-alpha employs a protein-tyrosine phosphatase to inhibit activation of hepatocyte growth factor receptor and hepatocyte growth factor-induced endothelial cell proliferation. Mol Cell Biochem 322, 113–117 (2009). https://doi.org/10.1007/s11010-008-9946-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-008-9946-7

Keywords

Search

Navigation