This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Micallef, M. J. Articles by Kurimoto, M. Search for Related Content PubMed PubMed Citation Articles by Micallef, M. J. Articles by Kurimoto, M.

Interleukin 18 Induces the Sequential Activation of Natural Killer Cells and Cytotoxic T Lymphocytes to Protect Syngeneic Mice from Transplantation with Meth A Sarcoma¹

Fujisaki Institute, Hayashibara Biochemical Laboratories Inc., Fujisaki 675-1, Okayama 702, Japan

We have recently reported that interleukin 18 (IL-18) pretreatment induces immunologically mediated antitumor effects in BALB/c mice injected i.p. with syngeneic Meth A sarcoma. In this study, mice were pretreated with IL-18 before Meth A transplantation, and immunocompetency in pretreated or untreated tumor-bearing mice (TBM) 3, 9, and 15 days after transplantation was compared with that of normal mice. On day 3, pretreated TBM mitogen-stimulated spleen cells produced significantly decreased levels of IL-2 and IFN- during 24-h culture. In contrast, IL-10 and granulocyte macrophage colony-stimulating factor productions were significantly enhanced in pretreated TBM cultures, and natural killer (NK) cell activity was also significantly augmented. Splenomegaly was also observed in the pretreated TBM on day 3, and the proliferating cells were identified as asialo GM1⁺ cells by flow cytometry. Cytotoxic activity of pretreated TBM spleen cells after a 5-day mixed lymphocytetumor cell culture did not differ from that of untreated TBM and normal mice on day 3 but was significantly enhanced on days 9 and 15 compared with that observed in normal mice and untreated TBM. Concurrently, the production of IL-2 and of IL-10 recovered and decreased, respectively, and NK activity dropped to normal levels. The effects of IL-18 on cytokine production and NK activity observed on day 3 treated TBM were also reproduced in normal mice. In conclusion, IL-18 seems to enhance the generation of NK activity early after tumor transplantation and simultaneously induces an increase and a decrease in the production of IL-10 and IL-2, respectively. As NK activity subsides to normal levels and IL-10 synthesis decreases, IL-2 synthesis is restored, and cytolytic cell activity is significantly enhanced. These results provide new insight into the immunologically mediated antitumor effects of IL-18.

¹ This work was supported in part by the Hayashibara Cancer Research Fellowship Program (M. J. M.).

² To whom requests for reprints should be addressed. Phone: 81-86-276-3141; Fax: 81-86-276-6885.

Received 4/29/97. Accepted 8/29/97.

This article has been cited by other articles:

				M. J. Robertson, J. M. Kirkwood, T. F. Logan, K. M. Koch, S. Kathman, L. C. Kirby, W. N. Bell, L. M. Thurmond, J. Weisenbach, and M. M. Dar A Dose-Escalation Study of Recombinant Human Interleukin-18 Using Two Different Schedules of Administration in Patients with Cancer Clin. Cancer Res., June 1, 2008; 14(11): 3462 - 3469. [Abstract] [Full Text] [PDF]

				H. K. Takahashi, G. Weitz-Schmidt, H. Iwagaki, T. Yoshino, N. Tanaka, and M. Nishibori Hypothesis: the antitumor activities of statins may be mediated by IL-18 J. Leukoc. Biol., August 1, 2006; 80(2): 215 - 216. [Abstract] [Full Text] [PDF]

				M. J. Robertson, J. W. Mier, T. Logan, M. Atkins, H. Koon, K. M. Koch, S. Kathman, L. N. Pandite, C. Oei, L. C. Kirby, et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4265 - 4273. [Abstract] [Full Text] [PDF]

				M. J. Smyth, J. Swann, J. M. Kelly, E. Cretney, W. M. Yokoyama, A. Diefenbach, T. J. Sayers, and Y. Hayakawa NKG2D Recognition and Perforin Effector Function Mediate Effective Cytokine Immunotherapy of Cancer J. Exp. Med., November 15, 2004; 200(10): 1325 - 1335. [Abstract] [Full Text] [PDF]

				T. Tatsumi, J. Huang, W. E. Gooding, A. Gambotto, P. D. Robbins, N. L. Vujanovic, S. M. Alber, S. C. Watkins, H. Okada, and W. J. Storkus Intratumoral Delivery of Dendritic Cells Engineered to Secrete Both Interleukin (IL)-12 and IL-18 Effectively Treats Local and Distant Disease in Association with Broadly Reactive Tc1-type Immunity Cancer Res., October 1, 2003; 63(19): 6378 - 6386. [Abstract] [Full Text] [PDF]

				Y. Luo, H. Zhou, M. Mizutani, N. Mizutani, R. A. Reisfeld, and R. Xiang Transcription factor Fos-related antigen 1 is an effective target for a breast cancer vaccine PNAS, July 22, 2003; 100(15): 8850 - 8855. [Abstract] [Full Text] [PDF]

				T. Tatsumi, A. Gambotto, P. D. Robbins, and W. J. Storkus Interleukin 18 Gene Transfer Expands the Repertoire of Antitumor Th1-type Immunity Elicited by Dendritic Cell-based Vaccines in Association with Enhanced Therapeutic Efficacy Cancer Res., October 15, 2002; 62(20): 5853 - 5858. [Abstract] [Full Text] [PDF]

				M. M. Borges, A. Campos-Neto, P. Sleath, K. H. Grabstein, P. J. Morrissey, Y. A. W. Skeiky, and S. G. Reed Potent Stimulation of the Innate Immune System by a Leishmania brasiliensis Recombinant Protein Infect. Immun., September 1, 2001; 69(9): 5270 - 5277. [Abstract] [Full Text] [PDF]

				Y.-I. Son, R. M. Dallal, R. B. Mailliard, S. Egawa, Z. L. Jonak, and M. T. Lotze Interleukin-18 (IL-18) Synergizes with IL-2 to Enhance Cytotoxicity, Interferon-{{gamma}} Production, and Expansion of Natural Killer Cells Cancer Res., February 1, 2001; 61(3): 884 - 888. [Abstract] [Full Text]

				G. Cai, R. Kastelein, and C. A. Hunter Interleukin-18 (IL-18) Enhances Innate IL-12-Mediated Resistance to Toxoplasma gondii Infect. Immun., December 1, 2000; 68(12): 6932 - 6938. [Abstract] [Full Text] [PDF]

				P. G. Arndt, G. Fantuzzi, and E. Abraham Expression of Interleukin-18 in the Lung after Endotoxemia or Hemorrhage-Induced Acute Lung Injury Am. J. Respir. Cell Mol. Biol., June 1, 2000; 22(6): 708 - 713. [Abstract] [Full Text]

				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]

				Y.-M. Kim, H.-S. Kang, S.-G. Paik, K.-H. Pyun, K. L. Anderson, B. E. Torbett, and I. Choi Roles of IFN Consensus Sequence Binding Protein and PU.1 in Regulating IL-18 Gene Expression J. Immunol., August 15, 1999; 163(4): 2000 - 2007. [Abstract] [Full Text] [PDF]

				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]

				N. Fujioka, R. Akazawa, K. Ohashi, M. Fujii, M. Ikeda, and M. Kurimoto Interleukin-18 Protects Mice against Acute Herpes Simplex Virus Type 1 Infection J. Virol., March 1, 1999; 73(3): 2401 - 2409. [Abstract] [Full Text]