Abstract
Purpose
Pro-interleukin-16 (pro-IL-16) is the precursor to mature interleukin-16 (IL-16) protein. Previous studies have demonstrated that pro-IL-16 can function as a regulator of cell cycle. A number of human T-cell leukemia and lymphoma cell lines are pro-IL-16 deficient. Intracellular expression of pro-IL-16 causes these cell lines to become quiescent, implicating loss of pro-IL-16 as a contributory step in T-cell malignancy. Therefore, we tested whether or not reintroduction of pro-IL-16 into solid tumors in mice could halt tumor growth.
Methods
MOLT-4 lymphoblastic leukemia cells were stably transfected with a dsRed-tomato virus and were injected subcutaneously into NOD/SCID/γ chain-knockout mice. Tumor growth was monitored with an in vivo imaging system. A pro-IL-16-GFP fusion virus or control GFP only virus was injected into the tumors, and mice were monitored for 1 week.
Results
Injection of the pro-IL-16-containing lentivirus inhibited growth of established MOLT-4 tumors in mice. Tumor explants exhibited diminished proliferative capacity.
Conclusions
Our data support the concept that restoration of pro-IL-16 expression in malignant T cells may have therapeutic value.
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References
Carrano AC, Eytan E et al (1999) SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1(4):193–199
Center DM, Cruikshank W (1982) Modulation of lymphocyte migration by human lymphokines. I. Identification and characterization of chemoattractant activity for lymphocytes from mitogen-stimulated mononuclear cells. J Immunol 128(6):2563–2568
Center DM, Cruikshank WW et al (2004) Nuclear pro-IL-16 regulation of T cell proliferation: p27(KIP1)-dependent G0/G1 arrest mediated by inhibition of Skp2 transcription. J Immunol 172(3):1654–1660
Cruikshank W, Center DM (1982) Modulation of lymphocyte migration by human lymphokines. II. Purification of a lymphotactic factor (LCF). J Immunol 128(6):2569–2574
Cruikshank WW, Berman JS et al (1987) Lymphokine activation of T4 + T lymphocytes and monocytes. J Immunol 138(11):3817–3823
Cruikshank WW, Center DM et al (1994) Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression. Proc Natl Acad Sci USA 91(11):5109–5113
Cruikshank WW, Kornfeld H et al (2000) Interleukin-16. J Leukoc Biol 67(6):757–766
Lynch EA, Heijens CA et al (2003) Cutting edge: IL-16/CD4 preferentially induces Th1 cell migration: requirement of CCR5. J Immunol 171(10):4965–4968
Muhlhahn P, Zweckstetter M et al (1998) Structure of interleukin 16 resembles a PDZ domain with an occluded peptide binding site. Nat Struct Biol 5(8):682–686
Ohsugi Y, Gershwin ME et al (1980) Tumorigenicity of human malignant lymphoblasts: comparative study with unmanipulated nude mice, antilymphocyte serum-treated nude mice, and X-irradiated nude mice. J Natl Cancer Inst 65(4):715–718
Richmond J, Tuzova M et al (2011) Interleukin-16 as a marker of Sezary syndrome onset and stage. J Clin Immunol 31(1): 39–50
Tsvetkov LM, Yeh KH et al (1999) p27(Kip1) ubiquitination and degradation is regulated by the SCF(Skp2) complex through phosphorylated Thr187 in p27. Curr Biol 9(12):661–664
Watanabe S, Shimosato Y et al (1980) Transplantability of human lymphoid cell line, lymphoma, and leukemia in splenectomized and/or irradiated nude mice. Cancer Res 40(7):2588–2595
Zhang Y, Tuzova M et al (2008) Pro-IL-16 recruits histone deacetylase 3 to the Skp2 core promoter through interaction with transcription factor GABP. J Immunol 180(1):402–408
Acknowledgments
Jillian Richmond is supported by a fellowship through the National Science Foundation 0538608. William Cruikshank is supported by the National Institutes of Health grant R01CA122737-01A2. We would like to thank Darrell Kotton for methods for generation of lentiviral constructs, Gustavo Mostoslavsky for providing the dsRed-tomato lentivirus, Yujun Zhang for providing input for preliminary studies, Chuanping Si and Marina Tuzova for technical assistance in generating the pro-IL-16 lentivirus, Constantina Christodoulou and Amel Omari for generating the GFP control lentivirus, and Peggy Russell for assistance with cell culture.
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The authors declare no conflict of interests.
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Whole-body animal imaging was acquired using equipment maintained by the Boston University Medical Campus Animal Imaging Core Facilities. All flow cytometric data were acquired using equipment maintained by the Boston University Medical Campus Flow Cytometry Core Facilities.
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Richmond, J., Finkel, M., Studwell, A. et al. Introduction of pro-interleukin-16 inhibits T-lymphoblastic leukemia growth in mice. J Cancer Res Clin Oncol 137, 1581–1585 (2011). https://doi.org/10.1007/s00432-011-1017-x
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DOI: https://doi.org/10.1007/s00432-011-1017-x