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-Inducing Factor/IL-18 Administration Mediates IFN-- and IL-12-Independent Antitumor Effects1
Departments of
*
Surgery and
Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213;
Division of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo; and
§
Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan
We evaluated the mechanism of the antitumor effects of mouse
rIFN-
-inducing factor/IL-18 protein on the growth of mouse tumor
cell lines in vivo. Mice received IL-18 before or after challenge with
CL8-1, a mouse melanoma cell line. Both regimens significantly
suppressed tumor growth and reduced the number of mice with growth of
tumor from 60% (3/5) to 20% (1/5). Furthermore, IL-18 administered
before and after tumor inoculation completely abrogated the
establishment of CL8-1 in all animals. IL-18 administration also
significantly suppressed the growth of MCA205, a sarcoma cell line,
even when treatment was delayed to 7 days following tumor inoculation.
Although IL-18/IL-12 combination therapy had the most significant and
immediate antitumor effects, many mice so treated succumbed with
markedly elevated serum IFN- levels. The antitumor effects of IL-18
were abrogated almost completely when NK cells were eliminated using
anti-asialo GM1 Ab administration, but only marginally impaired in
IFN- or IL-12 gene-disrupted mice. Immunohistochemical staining
revealed that the number of the CD8+ T cells, but not
CD4+ T cells, found at the tumor site was reduced in
animals treated with IL-18. These results indicate that IL-18 has
potent antitumor effects mediated by CD4+ T cells and NK
cells, but in IFN-- and IL-12-independent pathways.
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W. E. Carson, J. E. Dierksheide, S. Jabbour, M. Anghelina, P. Bouchard, G. Ku, H. Yu, H. Baumann, M. H. Shah, M. A. Cooper, et al. Coadministration of interleukin-18 and interleukin-12 induces a fatal inflammatory response in mice: critical role of natural killer cell interferon-gamma production and STAT-mediated signal transduction Blood, August 15, 2000; 96(4): 1465 - 1473. [Abstract] [Full Text] [PDF]
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D. Cho, H. Song, Y. M. Kim, D. Houh, D. Y. Hur, H. Park, D. Yoon, K. H. Pyun, W. J. Lee, M. Kurimoto, et al. Endogenous Interleukin-18 Modulates Immune Escape of Murine Melanoma Cells by Regulating the Expression of Fas Ligand and Reactive Oxygen Intermediates Cancer Res., May 1, 2000; 60(10): 2703 - 2709. [Abstract] [Full Text]
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S. Nakamura, T. Otani, Y. Ijiri, R. Motoda, M. Kurimoto, and K. Orita IFN-{gamma}-Dependent and -Independent Mechanisms in Adverse Effects Caused by Concomitant Administration of IL-18 and IL-12 J. Immunol., March 15, 2000; 164(6): 3330 - 3336. [Abstract] [Full Text] [PDF]
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J. Hein, V. A. J. Kempf, J. Diebold, N. Bucheler, S. Preger, I. Horak, A. Sing, U. Kramer, and I. B. Autenrieth Interferon Consensus Sequence Binding Protein Confers Resistance against Yersinia enterocolitica Infect. Immun., March 1, 2000; 68(3): 1408 - 1417. [Abstract] [Full Text] [PDF]
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J. S. Wild, A. Sigounas, N. Sur, M. S. Siddiqui, R. Alam, M. Kurimoto, and S. Sur IFN-{gamma}-Inducing Factor (IL-18) Increases Allergic Sensitization, Serum IgE, Th2 Cytokines, and Airway Eosinophilia in a Mouse Model of Allergic Asthma J. Immunol., March 1, 2000; 164(5): 2701 - 2710. [Abstract] [Full Text] [PDF]
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F. Vidal-Vanaclocha, G. Fantuzzi, L. Mendoza, A. M. Fuentes, M. J. Anasagasti, J. Martin, T. Carrascal, P. Walsh, L. L. Reznikov, S.-H. Kim, et al. IL-18 regulates IL-1beta -dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1 PNAS, January 18, 2000; 97(2): 734 - 739. [Abstract] [Full Text] [PDF]
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D. L. Martin, C. L. King, E. Pearlman, E. Strine, and F. P. Heinzel IFN-{gamma} Is Necessary But Not Sufficient for Anti-CD40 Antibody-Mediated Inhibition of the Th2 Response to Schistosoma mansoni Eggs J. Immunol., January 15, 2000; 164(2): 779 - 785. [Abstract] [Full Text] [PDF]
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K. Oshikawa, F. Shi, A. L. Rakhmilevich, P. M. Sondel, D. M. Mahvi, and N.-S. Yang Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1beta converting enzyme cDNA PNAS, November 9, 1999; 96(23): 13351 - 13356. [Abstract] [Full Text] [PDF]
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D. Ito, T. C. Back, A. N. Shakhov, R. H. Wiltrout, and S. A. Nedospasov Mice with a Targeted Mutation in Lymphotoxin-{alpha} Exhibit Enhanced Tumor Growth and Metastasis: Impaired NK Cell Development and Recruitment J. Immunol., September 1, 1999; 163(5): 2809 - 2815. [Abstract] [Full Text] [PDF]
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W. Hashimoto, T. Osaki, H. Okamura, P. D. Robbins, M. Kurimoto, S. Nagata, M. T. Lotze, and H. Tahara Differential Antitumor Effects of Administration of Recombinant IL-18 or Recombinant IL-12 Are Mediated Primarily by Fas-Fas Ligand- and Perforin-Induced Tumor Apoptosis, Respectively J. Immunol., July 15, 1999; 163(2): 583 - 589. [Abstract] [Full Text] [PDF]
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H. F. Staats and F. A. Ennis Jr. IL-1 Is an Effective Adjuvant for Mucosal and Systemic Immune Responses When Coadministered with Protein Immunogens J. Immunol., May 15, 1999; 162(10): 6141 - 6147. [Abstract] [Full Text] [PDF]
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H. Kojima, Y. Aizawa, Y. Yanai, K. Nagaoka, M. Takeuchi, T. Ohta, H. Ikegami, M. Ikeda, and M. Kurimoto An Essential Role for NF-{kappa}B in IL-18-Induced IFN-{gamma} Expression in KG-1 Cells J. Immunol., May 1, 1999; 162(9): 5063 - 5069. [Abstract] [Full Text] [PDF]
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