Abstract
To investigate the influence of tumor producing interleukin-5 (IL-5) on growth kinetics of tumors, we transduced the murine IL-5 gene into murine colon C26 tumor cells. Two IL-5-secreting clones, low-level IL-5 producer C26-8B and high-level IL-5 producer C26-6F, were established. Both tumors, C26-6F and C26-8B, grew more slowly than the mock C26 tumor, although the in vitro growth rate of these IL-5 transfectants was much the same as that of the mock C26 cells. There was a significantly decreased number of colonies in the lung of mice given C26-6F or C26-8B tumors i.v. than in mice given mock C26 tumors i.v. Moreover, in mice given C26-6F cells i.v., a smaller number of tumor colonies in the lung was observed, as compared to the case with C26-6B cells. While the growth rate of C26-8B tumors in mice treated with anti-IL-5 mAb was more rapid than that seen in control mAb-treated mice, growth of C26-6F tumors in anti-IL-5-mAb-treated mice was slightly more rapid compared to findings in control mAb-treated mice. The isotypematched mAb did not alter the in vitro growth of mock-C26 cells or of the IL-5-gene-modified C26 cells. Growth of IL-5-secreting C26 tumors transplanted in nude mice was also inhibited. These results suggest that tumor-producing IL-5 inhibits growth of colon tumors mediated through T-cell-independent protective mechanisms of the host.
Key words: IL-5, Gene transfection, Antitumor effect, Colon tumors
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.Blankenstein TH, Qin ZH, Li WQ, Diamantstein T. DNA rearrangement and constitutive expression of the interleukin 6 gene in a mouse plasmacytoma. J Exp Med. 1990;171:965. doi: 10.1084/jem.171.3.965. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Brattain MG, Strobel-Stevens J, Find D, Webb M, Strrif AM. Establishment of mouse colonic carcinoma cell lines with different metastatic properties. Cancer Res. 1980;40:2142. [PubMed] [Google Scholar]
- 5.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]
- 6.Karasuyama H, Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988;18:97. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
- 7.Kruger-Krasagakes S, Li WQ, Richter G, Diamantstein T, Blankenstein TH. Eosinophils infiltrating interleukin-5 genetransfected tumors do not suppress tumor grwoth. Eur J Immunol. 1993;23:992. doi: 10.1002/eji.1830230438. [DOI] [PubMed] [Google Scholar]
- 8.Martinez OM, Acher NL, Ferrell L, Villanueva J, Lake J, Roberts JP, Krams SM. Evidence for a nonclassical pathway of graft rejection involving interleukin 5 and eosinophils. Transplantation. 1993;55:909. doi: 10.1097/00007890-199304000-00041. [DOI] [PubMed] [Google Scholar]
- 9.Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983;65:55. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
- 10.Mullen CA, Coale MM, Levy AT, Stetler-Stevenson WG, Liotta LA, Brandt S, Blaese RM. Fibrosarcoma cells transduced with the IL-6 gene exhibited reduced tumorigenicity, increased immunogenicity, and decrease metastatic potential. Cancer Res. 1992;52:6020. [PubMed] [Google Scholar]
- 11.Nakashima Y, Mita S, Takatsu K, Ogawa M. Interleukin 5 induces tumor suppression by peritoneal exudate cells in mice. Cancer Immunol Immunother. 1993;37:227. doi: 10.1007/BF01518515. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Pretlow TW, Keith EF, Cryer AK, Bartolucci AA, Pitts AM, Pretlow TGII, Kimball PM, Boohaker EA. Eosinophil infiltration of human colonic carcinomas as a prognostic indicator. Cancer Res. 1983;43:2997. [PubMed] [Google Scholar]
- 13.Rivoltini L, Viggiano V, Spinazze S, Santoro A, Colombo MP, Takatsu K, Pamiani G. In vitro anti-tumor activity of eosinophils from cancer patients treated with subcutaneous administration of interleukin 2. Role of interleukin 5. Int J Cancer. 1993;54:8. doi: 10.1002/ijc.2910540103. [DOI] [PubMed] [Google Scholar]
- 14.Sanderson CJ, Cambell HD, Young IG. Molecular and cellular biology of eosinophils differentiation factor (IL-5) and its effect of human and mouse B cells. Immunol Rev. 1988;102:29. doi: 10.1111/j.1600-065x.1988.tb00740.x. [DOI] [PubMed] [Google Scholar]
- 15.Takaki S, Tominaga A, Hitoshi Y, Mita S, Sonoda E, Yamaguchi N, Takatsu K. Molecular cloning and expression of the murine interleukin-5 receptor. EMBO J. 1990;9:4367. doi: 10.1002/j.1460-2075.1990.tb07886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Takatsu K, Kikuchi Y, Takahashi 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, 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]
- 19.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]
- 20.Wu HK, Hirai H, Inamori K, Kitamura K, Takaku F. Antitumor effects of interleukin-4 and interleukin-5 against mouse B cell lymphoma and possible mechanisms of action. Jpn J Cancer Res. 1992;83:200. doi: 10.1111/j.1349-7006.1992.tb00087.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
