Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
International Journal of Oncology
Join Editorial Board Propose a Special Issue
Print ISSN: 1019-6439 Online ISSN: 1791-2423
Journal Cover
August 2012 Volume 41 Issue 2

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
August 2012 Volume 41 Issue 2

Full Size Image

Cover Legend PDF

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation

  • Authors:
    • Lining Zhu
    • Zhihui Zhao
    • Yanzhang Wei
    • William Marcotte
    • Thomas E. Wagner
    • Xianzhong Yu
  • View Affiliations / Copyright

    Affiliations: Department of Biological Sciences, Clemson University, Clemson, SC 29634, USA, Department of Animal Genetics and Breeding, Jilin University, Changchun 130062, P.R. China, Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA, Orbis Health Solutions, Greenville, SC 29607, USA
  • Pages: 661-669
    |
    Published online on: May 8, 2012
       https://doi.org/10.3892/ijo.2012.1466
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

The dependency of activated natural killer (NK) cells on the continuous support of exogenous interleukin (IL)-2 for their in vivo survival, tumor localization and consequently, their antitumor effect, is a major obstacle for NK cell-mediated tumor therapy. In the present study, a fusion gene between IL-12 and mouse sonic hedgehog C-terminal domain (Shh-C) was constructed. The fusion protein was autocatalytically processed to form cholesterol-modified IL-12 molecules and an autocrine loop of IL-12 was established for the sustained activation of NK cells. The transduced NK cells matured more rapidly in vitro with the enhanced expression of granule-related proteins. NKIL-12/Shh-C cells reached the same proliferation rate as NK cells transduced with enhanced green fluorescent protein (EGFP)/Shh-C (NKEGFP/Shh-C) with <10-fold IL-2 supplementation, suggesting that the fusion protein reduced the dependency of NK cells on IL-2. The amount of interferon‑γ (IFN-γ) in the supernatants of NKIL-12/Shh-C cells 5 and 7 days after transduction was significantly higher than that in the supernatants of NKIL-12 cells. Immunofluorescent staining of lung tissues from B16-bearing mice which had received an intravenous injection of lentivirus-transduced NK cells without exogenous IL-2 confirmed that donor NK cells successfully infiltrated into the lung tissues. The survival time of the mice which had received NKIL-12/Shh-C cells was significantly prolonged compared to the mice which had received NKEGFP/Shh-C cells.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

View References

1 

Moretta A, Bottino C, Mingari MC, Biassoni R and Moretta L: What is a natural killer cell? Nat Immunol. 3:6–8. 2002. View Article : Google Scholar

2 

Smyth MJ, Thia KY, Cretney E, et al: Perforin is a major contributor to NK cell control of tumor metastasis. J Immunol. 162:6658–6662. 1999.PubMed/NCBI

3 

Lauwerys BR, Garot N, Renauld JC and Houssiau FA: Cytokine production and killer activity of NK/T-NK cells derived with IL-2, IL-15, or the combination of IL-12 and IL-18. J Immunol. 165:1847–1853. 2000. View Article : Google Scholar : PubMed/NCBI

4 

Smith BR, Rosenthal DS and Ault KA: Natural killer lymphocytes in hairy cell leukemia: presence of phenotypically identifiable cells with defective functional activity. Exp Hematol. 13:189–193. 1985.

5 

Biron CA, Nguyen KB, Pien GC, Cousens LP and Salazar-Mather TP: Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol. 17:189–220. 1999. View Article : Google Scholar : PubMed/NCBI

6 

Rosenberg S: Lymphokine-activated killer cells: a new approach to immunotherapy of cancer. J Natl Cancer Inst. 75:595–603. 1985.PubMed/NCBI

7 

Trinchieri G, Matsumoto-Kobayashi M, Clark SC, Seehra J, London L and Perussia B: Response of resting human peripheral blood natural killer cells to interleukin 2. J Exp Med. 160:1147–1169. 1984. View Article : Google Scholar : PubMed/NCBI

8 

Goding SR, Yang Q, Knudsen KB, Potter DM and Basse PH: Cytokine gene therapy using adenovirally transduced, tumor-seeking activated natural killer cells. Hum Gene Ther. 18:701–711. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Rosenberg SA, Lotze MT, Muul LM, et al: Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 313:1485–1492. 1985. View Article : Google Scholar

10 

Yang Q, Hokland ME, Bryant JL, et al: Tumor-localization by adoptively transferred, interleukin-2-activated NK cells leads to destruction of well-established lung metastases. Int J Cancer. 105:512–519. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Loza MJ and Perussia B: The IL-12 signature: NK cell terminal CD56+high stage and effector functions. J Immunol. 172:88–96. 2004. View Article : Google Scholar : PubMed/NCBI

12 

Maas RA, Dullens HF and Den Otter W: Interleukin-2 in cancer treatment: disappointing or (still) promising? A review. Cancer Immunol Immunother. 36:141–148. 1993. View Article : Google Scholar : PubMed/NCBI

13 

Imboden M, Shi F, Pugh TD, et al: Safety of interleukin-12 gene therapy against cancer: a murine biodistribution and toxicity study. Hum Gene Ther. 14:1037–1048. 2003. View Article : Google Scholar : PubMed/NCBI

14 

Ji J, Li J, Holmes LM, et al: Glycoinositol phospholipid-anchored interleukin 2 but not secreted interleukin 2 inhibits melanoma yumor growth in mice. Mol Cancer Ther. 1:1019–1024. 2002.PubMed/NCBI

15 

Konstantinidis KV, Alici E, Aints A, Christensson B, Ljunggren HG and Dilber MS: Targeting IL-2 to the endoplasmic reticulum confines autocrine growth stimulation to NK-92 cells. Exp Hematol. 33:159–164. 2005. View Article : Google Scholar : PubMed/NCBI

16 

Gurdon JB and Bourillot PY: Morphogen gradient interpretation. Nature. 413:797–803. 2001. View Article : Google Scholar : PubMed/NCBI

17 

Cadigan KM: Regulating morphogen gradients in the Drosophila wing. Semin Cell Dev Biol. 13:83–90. 2002. View Article : Google Scholar : PubMed/NCBI

18 

Lawrence PA and Struhl G: Morphogens, compartments, and pattern: lessons from Drosophila? Cell. 85:951–961. 1996. View Article : Google Scholar : PubMed/NCBI

19 

Tabata T and Kornberg TB: Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell. 76:89–102. 1994. View Article : Google Scholar : PubMed/NCBI

20 

Teleman AA, Strigini M and Cohen SM: Shaping morphogen gradients. Cell. 105:559–562. 2001. View Article : Google Scholar : PubMed/NCBI

21 

Vincent JP and Dubois L: Morphogen transport along epithelia, an integrated trafficking problem. Dev Cell. 3:615–623. 2002. View Article : Google Scholar : PubMed/NCBI

22 

Mann RK and Beachy PA: Novel lipid modifications of secreted protein signals. Annu Rev Biochem. 73:891–923. 2004. View Article : Google Scholar : PubMed/NCBI

23 

Guerrero I and Chiang C: A conserved mechanism of Hedgehog gradient formation by lipid modifications. Trends Cell Biol. 17:1–5. 2007. View Article : Google Scholar : PubMed/NCBI

24 

Vincent S, Thomas A, Brasher B and Benson JD: Targeting of proteins to membranes through hedgehog auto-processing. Nat Biotechnol. 21:936–940. 2003. View Article : Google Scholar : PubMed/NCBI

25 

Sanda MG, Restifo NP, Walsh JC, et al: Molecular characterization of defective antigen processing in human prostate cancer. J Natl Cancer Inst. 87:280–285. 1995. View Article : Google Scholar : PubMed/NCBI

26 

Robertson MJ and Ritz J: Biology and clinical relevance of human natural killer cells. Blood. 76:2421–2438. 1990.PubMed/NCBI

27 

Albertsson PA, Basse PH, Hokland M, et al: NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity. Trends Immunol. 24:603–609. 2003. View Article : Google Scholar : PubMed/NCBI

28 

Basse PH, Whiteside TL and Herberman RB: Cancer immunotherapy with interleukin-2-activated natural killer cells. Mol Biotechnol. 21:161–170. 2002. View Article : Google Scholar : PubMed/NCBI

29 

Law TM, Motzer RJ, Mazumdar M, et al: Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer. 76:824–832. 1995. View Article : Google Scholar : PubMed/NCBI

30 

Kammula US, White DE and Rosenberg SA: Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer. 83:797–805. 1998. View Article : Google Scholar : PubMed/NCBI

31 

Herberman RB, Reynolds CW and Ortaldo JR: Mechanism of cytotoxicity by natural Killer (NK) cells. Annu Rev Immunol. 4:651–680. 1986. View Article : Google Scholar : PubMed/NCBI

32 

Skoskiewicz MJ, Colvin RB, Schneeberger EE and Russell PS: Widespread and selective induction of major histocompatibility complex-determined antigens in vivo by gamma interferon. J Exp Med. 162:1645–1664. 1985. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Zhu L, Zhao Z, Wei Y, Marcotte W, Wagner TE and Yu X: An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation. Int J Oncol 41: 661-669, 2012.
APA
Zhu, L., Zhao, Z., Wei, Y., Marcotte , W., Wagner, T.E., & Yu, X. (2012). An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation. International Journal of Oncology, 41, 661-669. https://doi.org/10.3892/ijo.2012.1466
MLA
Zhu, L., Zhao, Z., Wei, Y., Marcotte , W., Wagner, T. E., Yu, X."An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation". International Journal of Oncology 41.2 (2012): 661-669.
Chicago
Zhu, L., Zhao, Z., Wei, Y., Marcotte , W., Wagner, T. E., Yu, X."An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation". International Journal of Oncology 41, no. 2 (2012): 661-669. https://doi.org/10.3892/ijo.2012.1466
Copy and paste a formatted citation
x
Spandidos Publications style
Zhu L, Zhao Z, Wei Y, Marcotte W, Wagner TE and Yu X: An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation. Int J Oncol 41: 661-669, 2012.
APA
Zhu, L., Zhao, Z., Wei, Y., Marcotte , W., Wagner, T.E., & Yu, X. (2012). An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation. International Journal of Oncology, 41, 661-669. https://doi.org/10.3892/ijo.2012.1466
MLA
Zhu, L., Zhao, Z., Wei, Y., Marcotte , W., Wagner, T. E., Yu, X."An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation". International Journal of Oncology 41.2 (2012): 661-669.
Chicago
Zhu, L., Zhao, Z., Wei, Y., Marcotte , W., Wagner, T. E., Yu, X."An IL-12/Shh-C domain fusion protein-based IL-12 autocrine loop for sustained natural killer cell activation". International Journal of Oncology 41, no. 2 (2012): 661-669. https://doi.org/10.3892/ijo.2012.1466
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team