Abstract
The antitumor activity of peritoneal exudate cells (PEC) induced by murine interleukin-5 (mIL-5) was examined using Meth-A sarcoma cells transplanted into the peritoneal cavity of mice. Although in vitro treatment of Meth-A sarcoma cells with mIL-5 did not result in inhibition of their growth, treatment of mice intraperitoneally with mIL-5 (1 μg/day) from day −5 to +5 (tumor cells were inoculated on day 0) led to a significant increase in survival or even rejection of tumor cells. This antitumor effect depended on the dose of mIL-5. Interestingly, there was identical therapeutic activity when the protocol of days −10 to −1 was used as opposed to −5 to +5. In addition, post-treatment with mIL-5 from day +1 to +10 was ineffective. This suggests that the therapeutic activity of IL-5 is largely prophylactic. Under the former condition, the number of PEC was found to increase over 50-fold when compared to levels in control mice. Moreover, the antitumor effect of mIL-5 was completely abolished by subcutaneous injection of anti-mIL-5 monoclonal antibodies. The treatment of mice injected intraperitoneally with human IL-2 also resulted in an increase in survival. Winn assay experiments using PEC recovered from mIL-5-treated mice (1μg/day, from day −10 to −1) revealed that these PEC could mediate antitumor activity against Meth-A sarcoma cells. Furthermore, when the cured mice were re-injected with Meth-A sarcoma cells or syngeneic MOPC 104E cells, they could reject Meth-A sarcoma cells but not MOPC 104E cells, indicating that immune memory had been generated. These results suggest that IL-5 augumented the PEC tumoricidal activity but we have no indication that the tumoricidal activity was mediated through a mIL-5-dependent mechanism.
Key words: Interleukin-5, Antitumor activity, Eosinophils, Peritoneal exudate cells
References
- 1.Aoki T, Kikuchi H, Miyatake S, Oda Y, Iwasaki K, Yamasaki T, Kinashi T, Honjo T. Interleukin 5 enhances interleukin 2-mediated lymphokine-activated killer activity. J Exp Med. 1989;70:583. doi: 10.1084/jem.170.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Blankenstein TH, Li WQ, Uberia K, Qin Z, Tominaga A, Takatsu K, Yamaguchi N, Diamanstein T. Retroviral interleukin 5 gene transfer into interleukin 5-dependent growing cell lines results in autocrine growth and tumorigenicity. Eur J Immunol. 1990;20:2699. doi: 10.1002/eji.1830201226. [DOI] [PubMed] [Google Scholar]
- 3.Blick M, Sherwin SA, Rosenblum M, Gutterman J. Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res. 1987;47:2986. [PubMed] [Google Scholar]
- 4.Ciolli V, Gabriele L, Sestili P, Varano I, Proitetti E, Gresser I, Testa U, Montesoro E, Bulgarini D, Mariani G, Peschle C, Belardelli F. Combined interleukin 1/interleukin 2 therapy of mice injected with highly metastatic friend leukemia cells: host antitumor mechanisms and marked effects on established metastasis. J Exp Med. 1991;173:313. doi: 10.1084/jem.173.2.313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Crown J, Jakubowski A, Kemeny N, Gordon M, Gasparetto C, Wong G, Sheridan C, Toner G, Meisenberg B, Botet J, Applewhite J, Sinha S, Moore M, Kelsen D, Buhles W, Gabrilove J. A phase I trial of recombinant human interleukin-1ß alone and in combination with myelosuppressive doses of 5-fluorouracil in patients with gastrointestincal cancer. Blood. 1991;78:1420. [PubMed] [Google Scholar]
- 6.Dent LA, Strath M, Andrew LM, Sanderson CJ. Eosinophilia in transgenic mice expressing interleukin 5. J Exp Med. 1990;172:1425. doi: 10.1084/jem.172.5.1425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Fujioka T, Ishikura K, Tanji S, Okamoto T, Koike H, Aoki H, Ohhori T, Kubo T. Combined effects of intraperitoneal administration of recombinant interleukin-2 and streptococcal preparation CK-432 in murine tumors. Int J Immunopharmacol. 1990;12:419. doi: 10.1016/0192-0561(90)90025-i. [DOI] [PubMed] [Google Scholar]
- 8.Golumbek PT, Lazenby AJ, Levitsky HI, Jaffee LM, Karasuyama H, Baker M, Pardoll DM. Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science. 1991;254:713. doi: 10.1126/science.1948050. [DOI] [PubMed] [Google Scholar]
- 9.Harada N, Takahashi T, Matsumoto M, Kinashi T, Ohara J, Kikuchi Y, Koyama N, Severinson E, Yaoita Y, Honjo T, Yamaguchi Y, Tominaga A, Takatsu K. Production of a monoclonal antibody useful in the molecular characterization of murine T-cell-replacing factor/B-cell growth factor II. Proc Natl Acad Sci USA. 1987;84:4581. doi: 10.1073/pnas.84.13.4581. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Hitoshi Y, Yamaguchi N, Korenaga M, Mita S, Tominaga T, Takatsu K. In vivo administration of antibody to murine IL-5 receptor inhibits eosinophilia of IL-5 transgenic mice. Int Immunol. 1991;3:135. doi: 10.1093/intimm/3.2.135. [DOI] [PubMed] [Google Scholar]
- 11.Macdonald D, Gordon AA, Kajitani H, Enokihara H, Barrett AJ. Interleukin-2 treatment-associated eosinophilia is mediated by interleukin-5 production. Br J Haematol. 1990;76:168. doi: 10.1111/j.1365-2141.1990.tb07867.x. [DOI] [PubMed] [Google Scholar]
- 12.Mita S, Tominaga A, Hitoshi Y, Sakamoto K, Honjo T, Akagi M, Kikuchi Y, Yamaguchi N, Takatsu K. Characterization of high affinity receptors for interleukin 5 on interleukin 5-dependent cell lines. Proc Natl Acad Sci USA. 1989;86:2311. doi: 10.1073/pnas.86.7.2311. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Palladino MA, Jr, Shalaby MR, Kramer SM, Ferraiolo BL, Baughman RA, Deleo AB, Crase D, Marafino B, Aggarwal BB, Figari IS, Liggitt D, Patton JS. Characterization of the antitumor activities of human tumor necrosis factor-α and the comparison with other cytokines: induction of tumor-specific immunity. J Immunol. 1987;138:4023. [PubMed] [Google Scholar]
- 14.Rosenberg SA, Lotze MT, Muu LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Reichert CM. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485. doi: 10.1056/NEJM198512053132327. [DOI] [PubMed] [Google Scholar]
- 15.Sanderson CJ, Campbell HD, Young IG. Molecular and cellular biology of eosinophils differentiation factor (IL-5) and its effect on human and mouse B cells. Immunol Rev. 1988;102:29. doi: 10.1111/j.1600-065x.1988.tb00740.x. [DOI] [PubMed] [Google Scholar]
- 16.Takatsu K, Kikuchi Y, Takahashi T, Honjo T, Matsumoto M, Harada N, Yamaguchi N, Tominaga A. Interleukin 5, a T-cell-derived B-cell differentiation factor also induces cytotoxic T lymphocytes. Proc Natl Acad Sci USA. 1987;84:4234. doi: 10.1073/pnas.84.12.4234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Takatsu K, Tominaga A, Harada N, Mita S, Matsumoto M, Takahashi T, Kikuchi Y, Yamaguchi N. T cell-replacing factor (TRF)/interleukin 5 (IL-5): molecular and functional properties. Immunol Rev. 1988;102:107. doi: 10.1111/j.1600-065x.1988.tb00743.x. [DOI] [PubMed] [Google Scholar]
- 18.Tepper RI, Pattengale PK, Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell. 1989;57:503. doi: 10.1016/0092-8674(89)90925-2. [DOI] [PubMed] [Google Scholar]
- 19.Tepper RI, Coffman RL, Leder P. An eosinophil-dependent mechanism for the antitumor effect of interleukin-4. Science. 1992;257:548. doi: 10.1126/science.1636093. [DOI] [PubMed] [Google Scholar]
- 20.Tominaga A, Takaki S, Koyama N, Katoh S, Matsumoto R, Migita M, Hitoshi Y, Hosoya Y, Yamauchi S, Kanai Y, Miyazaki J-I, Usuku G, Yamamura K-I, Takatsu K. Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production. J Exp Med. 1991;173:429. doi: 10.1084/jem.173.2.429. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Unkeless JC. Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte FcR receptors. J Exp Med. 1979;150:580. doi: 10.1084/jem.150.3.580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Walsh GM, Hartnell A, Wardlaw AJ, Kurihara K, Sanderson CJ. IL-5 enhances the in vitro adhesion of human eosinophils, but not neutrophils, in a leucocyte integrin (CD11/18)-dependent manner. Immunology. 1990;71:258. [PMC free article] [PubMed] [Google Scholar]
- 23.Wu HK, Hirai H, Inamori K, Kitamura K, Takaku F. Anti-tumor effects of interleukin-4, and interleukin-5 against mouse B cell lymphoma and possible mechanisms of their action. Jpn J Cancer Res. 1992;83:200. doi: 10.1111/j.1349-7006.1992.tb00087.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Yamaguchi N, Hitoshi Y, Mita S, Hosoya Y, Murata Y, Kukuchi Y, Tominaga A, Takatsu K. Characterization of the murine interleukin 5 receptor by using a monoclonal antibody. Int Immunol. 1990;2:181. doi: 10.1093/intimm/2.2.181. [DOI] [PubMed] [Google Scholar]
- 25.Yamaguchi Y, Suda T, Shiozaki H, Miura Y, Hitoshi Y, Tominaga A, Takatsu K, Kasahara T. Role of IL-5 in IL-2-induced eosinophilia. In vivo and in vitro expression of IL-5 mRNA by IL-2. J Immunol. 1990;145:873. [PubMed] [Google Scholar]
