Skip to main content

Advertisement

SpringerLink
Log in

Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

During mammary tumorigenesis, there is a profound thymic involution associated with severe depletion of the most abundant subset of thymocytes, CD4+CD8+ immature cells, and an early arrest in at least two steps of T cell differentiation. Thymic atrophy that is normally related with aging has been observed in other model systems, including graft-vs-host disease (GVHD) and tumor development. However, the mechanisms involved in this phenomenon remain to be elucidated. Vascular endothelial growth factor (VEGF) has been associated with thymic involution, when expressed at high levels systemically. In thymuses of D1-DMBA-3 tumor-bearing mice, this growth factor is diminished relative to the level of normal thymuses. Interestingly, the expression of hepatocyte growth factor (HGF), which has been associated with proliferation, cell survival, angiogenesis and B-cell differentiation, is profoundly down-regulated in thymuses of tumor bearers. In parallel, IL-7 and IL-15 mRNA, crucial cytokines involved in thymocytes development and cellular homeostasis, respectively, are also down-regulated in the thymuses of tumor hosts as compared to those of normal mice. Injection of HGF into mice implanted with mammary tumors resulted in normalization of thymic volume and levels of VEGF, IL-7 and IL-15. While, injections of IL-7 partially restored the thymic involution observed in the thymuses of tumor-bearing mice, injection of IL-15 did not have any significant effects. Our data suggest that the downregulation of HGF and IL-7 may play an important role in the thymic involution observed in tumor-bearing hosts.

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
Fig. 8

Similar content being viewed by others

Abbreviations

NM:

Normal mice

TBM:

Tumor-bearing mice

HGF:

Hepatocyte growth factor

VEGF:

Vascular endothelial growth factor

References

  1. Gill J, Malin M, Sutherland J, Gray D, Hollander G, Boyd R (2003) Thymic generation and regeneration. Immunol Rev 195:28–50

    Article  PubMed  CAS  Google Scholar 

  2. Anderson G, Harman BC, Hare KJ, Jenkinson EJ (2000) Microenvironmental regulation of T cell development in the thymus. Semin Immunol 12:457–464

    Article  PubMed  CAS  Google Scholar 

  3. Ladi E, Yin X, Chtanova T, Robey EA (2006) Thymic microenvironments for T cell differentiation and selection. Nat Immunol 7:338–343

    Article  PubMed  CAS  Google Scholar 

  4. Takahama Y (2006) Journey through the thymus: stromal guides for T-cell development and selection. Nat Rev Immunol 6:127–135

    Article  PubMed  CAS  Google Scholar 

  5. Boyd E (1932) The weight of the thymus gland in health and disease. Am J Dis Child 43:1162–1214

    Google Scholar 

  6. Metcalf D, Moulds R, Pike B (1967) Influence of the spleen and thymus on immune responses in ageing mice. Clin Exp Immunol 2:109–120

    PubMed  CAS  Google Scholar 

  7. Aspinall R, Andrew D (2000) Thymic involution in aging. J Clin Immunol 20:250–256

    Article  PubMed  CAS  Google Scholar 

  8. Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133–139

    Article  PubMed  CAS  Google Scholar 

  9. Lapp WS, Ghayur T, Mendes M, Seddik M, Seemayer TA (1985) The functional and histological basis for graft-versus-host-induced immunosuppression. Immunol Rev 88:107–133

    Article  PubMed  CAS  Google Scholar 

  10. Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP (2000) The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol 18:529–560

    Article  PubMed  CAS  Google Scholar 

  11. Montecino-Rodriquez E, Min H, Dorshkind K (2005) Reevaluating current models of thymic involution. Semin Immunol 17:356–361

    Article  PubMed  CAS  Google Scholar 

  12. Medina D, DeOme KB (1969) Response of hyperplastic alveolar nodule outgrowth-line D1 to mammary tumor virus, nodule-inducing virus, and prolonged hormonal stimulation acting singly and in combination. J Natl Cancer Inst 42:303–310

    PubMed  CAS  Google Scholar 

  13. Fu YX, Altman N, Lopez DM (1989) Thymic atrophy induced by murine mammary adenocarcinoma in vivo. In Vivo 3:1–5

    PubMed  CAS  Google Scholar 

  14. Fu Y, Paul RD, Wang Y, Lopez DM (1989) Thymic involution and thymocyte phenotypic alterations induced by murine mammary adenocarcinomas. J Immunol 143:4300–4307

    PubMed  CAS  Google Scholar 

  15. Adkins B, Charyulu V, Sun QL, Lobo D, Lopez DM (2000) Early block in maturation is associated with thymic involution in mammary tumor-bearing mice. J Immunol 164:5635–5640

    PubMed  CAS  Google Scholar 

  16. Carrio R, Lopez DM (2009) Impaired thymopoiesis occurring during the thymic involution of tumor-bearing mice is associated with a down-regulation of the antiapoptotic proteins Bcl-XL and A1. Int J Mol Med 23:89–98

    PubMed  CAS  Google Scholar 

  17. Ohm JE, Gabrilovich DI, Sempowski GD, Kisseleva E, Parman KS, Nadaf S, Carbone DP (2003) VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 101:4878–4886

    Article  PubMed  CAS  Google Scholar 

  18. Imado T, Iwasaki T, Kataoka Y, Kuroiwa T, Hara H, Fujimoto J, Sano H (2004) Hepatocyte growth factor preserves graft-versus-leukemia effect and T-cell reconstitution after marrow transplantation. Blood 104:1542–1549

    Article  PubMed  CAS  Google Scholar 

  19. Miyazawa K, Tsubouchi H, Naka D, Takahashi K, Okigaki M, Arakaki N, Nakayama H, Hirono S, Sakiyama O, Takahashi K et al (1989) Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. Biochem Biophys Res Commun 163:967–973

    Article  PubMed  CAS  Google Scholar 

  20. Zarnegar R, Michalopoulos GK (1995) The many faces of hepatocyte growth factor: from hepatopoiesis to hematopoiesis. J Cell Biol 129:1177–1180

    Article  PubMed  CAS  Google Scholar 

  21. Carrio R, Bathe OF, Malek TR (2004) Initial antigen encounter programs CD8+ T cells competent to develop into memory cells that are activated in an antigen-free, IL-7- and IL-15-rich environment. J Immunol 172:7315–7323

    PubMed  CAS  Google Scholar 

  22. Carrio R, Lopez-Hoyos M, Jimeno J, Benedict MA, Merino R, Benito A, Fernandez-Luna JL, Nunez G, Garcia-Porrero JA, Merino J (1996) A1 demonstrates restricted tissue distribution during embryonic development and functions to protect against cell death. Am J Pathol 149:2133–2142

    PubMed  CAS  Google Scholar 

  23. Jin H, Carrio R, Yu A, Malek TR (2004) Distinct activation signals determine whether IL-21 induces B cell costimulation, growth arrest, or Bim-dependent apoptosis. J Immunol 173:657–665

    PubMed  CAS  Google Scholar 

  24. Yang J, Dai C, Liu Y (2001) Systemic administration of naked plasmid encoding hepatocyte growth factor ameliorates chronic renal fibrosis in mice. Gene Ther 8:1470–1479

    Article  PubMed  CAS  Google Scholar 

  25. Osaka G, Carey K, Cuthbertson A, Godowski P, Patapoff T, Ryan A, Gadek T, Mordenti J (1996) Pharmacokinetics, tissue distribution, and expression efficiency of plasmid [33P]DNA following intravenous administration of DNA/cationic lipid complexes in mice: use of a novel radionuclide approach. J Pharm Sci 85:612–618

    Article  PubMed  CAS  Google Scholar 

  26. Owen JL, Iragavarapu-Charyulu V, Gunja-Smith Z, Herbert LM, Grosso JF, Lopez DM (2003) Up-regulation of matrix metalloproteinase-9 in T lymphocytes of mammary tumor bearers: role of vascular endothelial growth factor. J Immunol 171:4340–4351

    PubMed  CAS  Google Scholar 

  27. Van Belle E, Witzenbichler B, Chen D, Silver M, Chang L, Schwall R, Isner JM (1998) Potentiated angiogenic effect of scatter factor/hepatocyte growth factor via induction of vascular endothelial growth factor: the case for paracrine amplification of angiogenesis. Circulation 97:381–390

    PubMed  Google Scholar 

  28. Gille J, Khalik M, Konig V, Kaufmann R (1998) Hepatocyte growth factor/scatter factor (HGF/SF) induces vascular permeability factor (VPF/VEGF) expression by cultured keratinocytes. J Invest Dermatol 111:1160–1165

    Article  PubMed  CAS  Google Scholar 

  29. Wojta J, Kaun C, Breuss JM, Koshelnick Y, Beckmann R, Hattey E, Mildner M, Weninger W, Nakamura T, Tschachler E, Binder BR (1999) Hepatocyte growth factor increases expression of vascular endothelial growth factor and plasminogen activator inhibitor-1 in human keratinocytes and the vascular endothelial growth factor receptor flk-1 in human endothelial cells. Lab Invest 79:427–438

    PubMed  CAS  Google Scholar 

  30. Sun QL, Charyulu V, Lobo D, Lopez DM (2002) Role of thymic stromal cell dysfunction in the thymic involution of mammary tumor-bearing mice. Anticancer Res 22:91–96

    PubMed  Google Scholar 

  31. Watson GA, Fu YX, Lopez DM (1991) Splenic macrophages from tumor-bearing mice co-expressing MAC-1 and MAC-2 antigens exert immunoregulatory functions via two distinct mechanisms. J Leukoc Biol 49:126–138

    PubMed  CAS  Google Scholar 

  32. Fu YX, Watson G, Jimenez JJ, Wang Y, Lopez DM (1990) Expansion of immunoregulatory macrophages by granulocyte-macrophage colony-stimulating factor derived from a murine mammary tumor. Cancer Res 50:227–234

    PubMed  CAS  Google Scholar 

  33. Lopez DM, Lopez-Cepero M, Watson GA, Ganju A, Sotomayor E, Fu YX (1991) Modulation of the immune system by mammary tumor-derived factors. Cancer Invest 9:643–653

    Article  PubMed  CAS  Google Scholar 

  34. Calderon C, Huang ZH, Gage DA, Sotomayor EM, Lopez DM (1994) Isolation of a nitric oxide inhibitor from mammary tumor cells and its characterization as phosphatidyl serine. J Exp Med 180:945–958

    Article  PubMed  CAS  Google Scholar 

  35. Aherne WA, Zaitoun AM, Lauder I, Hull DL (1980) Cytokinetic changes in the thymus of tumour-bearing and of dexamethasone-treated mice. Cell Tissue Kinet 13:485–495

    PubMed  CAS  Google Scholar 

  36. Taub DD, Longo DL (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72–93

    Article  PubMed  CAS  Google Scholar 

  37. Min H, Montecino-Rodriguez E, Dorshkind K (2006) Reassessing the role of growth hormone and sex steroids in thymic involution. Clin Immunol 118:117–123

    Article  PubMed  CAS  Google Scholar 

  38. Hadden JW (1998) Thymic endocrinology. Ann N Y Acad Sci 840:352–358

    Article  PubMed  CAS  Google Scholar 

  39. Huang Y, Chen X, Dikov MM, Novitskiy SV, Mosse CA, Yang L, Carbone DP (2007) Distinct roles of VEGFR-1 and VEGFR-2 in the aberrant hematopoiesis associated with elevated levels of VEGF. Blood 110:624–631

    Article  PubMed  CAS  Google Scholar 

  40. Porter BO, Malek TR (2000) Thymic and intestinal intraepithelial T lymphocyte development are each regulated by the gammac-dependent cytokines IL-2, IL-7, and IL-15. Semin Immunol 12:465–474

    Article  PubMed  CAS  Google Scholar 

  41. Ma A, Koka R, Burkett P (2006) Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 24:657–679

    Article  PubMed  CAS  Google Scholar 

  42. Zamisch M, Moore-Scott B, Su DM, Lucas PJ, Manley N, Richie ER (2005) Ontogeny and regulation of IL-7-expressing thymic epithelial cells. J Immunol 174:60–67

    PubMed  CAS  Google Scholar 

  43. Carrio R, Rolle CE, Malek TR (2007) Non-redundant role for IL-7R signaling for the survival of CD8+ memory T cells. Eur J Immunol 37:3078–3088

    Article  PubMed  CAS  Google Scholar 

  44. Lai L, Goldschneider I (2001) Cutting edge: identification of a hybrid cytokine consisting of IL-7 and the beta-chain of the hepatocyte growth factor/scatter factor. J Immunol 167:3550–3554

    PubMed  CAS  Google Scholar 

  45. Lai L, Zeff RA, Goldschneider I (2006) A recombinant single-chain IL-7/HGFbeta hybrid cytokine induces juxtacrine interactions of the IL-7 and HGF (c-Met) receptors and stimulates the proliferation of CFU-S12, CLPs, and pre-pro-B cells. Blood 107:1776–1784

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank to Dr. Howard T. Petrie for giving us his unpublished data cited in this paper as a personal communication. We thank Mantley Dorsey, Jr. for his technical assistance in the tumor implantation procedures and Dan Ilkovitch and Lynn Herbert for the helpful comments and discussions in preparing the manuscript. We thank Dr. Thomas R. Malek and Dr. Becky Adkins for critical reading of this manuscript. This research was supported by National Institutes of Health Grant RO1 CA25583.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, P.O. Box 016960, Miami, FL, 33101, USA

    Roberto Carrio & Diana M. Lopez

  2. Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA

    Norman H. Altman

Authors
  1. Roberto Carrio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Norman H. Altman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diana M. Lopez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Diana M. Lopez.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carrio, R., Altman, N.H. & Lopez, D.M. Downregulation of interleukin-7 and hepatocyte growth factor in the thymic microenvironment is associated with thymus involution in tumor-bearing mice. Cancer Immunol Immunother 58, 2059–2072 (2009). https://doi.org/10.1007/s00262-009-0714-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-009-0714-7

Keywords

Search

Navigation