Abstract
IL-6 is a multifunctional cytokine involved in differentiation and proliferation of immune cells. Moreover, it has diverse effects on the proliferation of tumor cells in vivo and in vitro. Although stimulating cell growth of multiple myeloma cells, it inhibits the proliferation of B16 melanoma cells and lung cancer cells. B9.55 cells, B-cell lymphoma, are IL-6-dependent cells, definitely requiring exogenous IL-6 for growth. When the cDNA for IL-6 was transfected into B9.55 cells, they began growing in an autocrine pattern without exogenous IL-6. To investigate the effects of IL-6 on B9.55 lymphoma in vivo, IL-6-transfected B9.55 cells (B9.G7) or neotransfected B9.55 cells (B9.vec) were injected subcutaneously into syngeneic mice. Initially, B9.G7 outgrew B9.vec, but after 3 weeks, B9.G7 grew slower than B9.vec. In addition, 5 µg of recombinant human IL-6 was injected daily into the tumor site. Reduced tumor sizes of IL-6-treated rats, similar to those observed in mice which received B9.G7, indicated that IL-6 itself is the mediator of tumor regression. When B9.G7 cells were injected into the irradiated normal mice, tumor regression was released compared with the untreated normal control, suggesting that radiosensitive host components were involved in the regression of B9.G7 cell growth. However, the tumor regression of B9.G7 cells was not released in SCID mice. Histologically, B9.G7 tumor demonstrated severe necrosis and apoptotic cells with infiltration of host inflammatory cells. Above data indicate that IL-6 functions as an autocrine growth factor for B9.G7 cells in vitro, but behaves as an autocrine inhibiting factor in vivo. These contrasting effects of IL-6 on tumor cells in vitro and in vivo will be facilitative in understanding the interaction of cytokines and host immune systems.
Similar content being viewed by others
References
Colombo MP, Forni G. Cytokine gene transfer in tumor inhibition and tumor therapy: where are we now? Immunol Today 15:48–51;1994.
Gansbacher B, Zier K, Daniel B, Cronin K, Bannerji R, Giboa E. Interleukin 2 gene transfer into tumor cells aborates tumorigenicity and induces protective immunity. J Exp Med 172:1217–1224;1990.
Connor J, Bannerji R, Saito S, Heston W, Fair W, Gilboa E. Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells. J Exp Med 177:1127–1134;1993.
Ley V, Langlade-Demoyen P, Kourlisky P, Larsson-Sciard EL. Interleukin 2-dependent activation of tumor-specific cytotoxic T lymphocytes in vivo. Eur J Immunol 21:851–854;1991.
Tepper RI, Pattengale PK, Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell 57:503–512;1989.
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 254:713–716;1991.
Esumi N, Hunt B, Itaya T, Frost P. Reduced tumorigenicity of murine tumor cells secreting γ-interferon is due to nonspecific host responses and is unrelated to class I major histocompatibility complex expression. Cancer Res 51:1185–1189;1991.
Porgado A, Bannerji R, Watanaba Y, Feldman M, Gilboa E, Eisembach L. Antimetastatic vaccination of tumor-bearing mice with two types of IFN-γ gene-inserted tumor cells. J Immunol 150:1458–1470;1993.
Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kishiwamura S, Najajima K, Koyama K, Iwamutsa A, Tsurawasa S, Sakiyama F, Matsui H, Takahara Y, Taniguchi T, Kishimoto T. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76;1986.
Hirano T, Taga T, Nakano N, Yasukawa K, Kishiwamura S, Shimizu K, Nakajima K, Pyun KH, Kishimoto T. Purification to homogeneity and characterization of human B cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci USA 82:5490–5494;1987.
Marinkovic S, Jahreis GP, Wong G, Baumann H. IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo. J Immunol 142:808–812;1989.
Sato T, Nakamura S, Taga T, Matsuda T, Hirano T, Kishimoto T, Kaziro Y. Induction of neuronal differentiation of PC12 cells by B cell stimulatory factor 2/interleukin 6. Mol Cell Biol 8:3346–3349;1988.
Klein B, Zhang XG, Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 73:517;1989.
Kang HS, Lee BS, Yang Y, Park CW, Ha HJ, Pyun KH, Choi I. Roles of protein phosphatase 1 and 2A in an IL-6-mediated autocrine growth loop of human myeloma cells. Cell Immunol 168:174–183;1996.
Miki S, Iswano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T, Kishimoto T. Interleukin-6 functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett 250:607–610;1989.
Chen L, Mory Y, **lberstein A, Revel M. Growth inhibition of human breast carcinoma and leukemia/lymphoma cell lines by recombinant interleukin-β2. Proc Natl Acad Sci USA 85:8037–8041;1988.
Mule JJ, McIntosh JK, Jablons DM, Rosenberg SA. Antitumor activity of recombinant interleukin 6 in mice. J Exp Med 171:629–636;1990.
Sun WH, Kreisle RA, Phillips AW, Ershler WB. In vivo and in vitro characteristics of interleukin 6-transfected B16 melanoma cells. Cancer Res 52:5412–5415;1992.
Takizawa H, Ohtishi T, Ohta K, Yamashita N, Hirohata S, Hirai K, Hiramatsu K, Ito K. Growth inhibition of human lung cancer cell lines by interleukin 6 in vitro: A possible roles in tumor growth via an autocrine mechanism. Cancer Res 53:4175–4181;1993.
Mullen CA, Coale MM, Levy AT, Stetler-Stevenson WG, Liotta LA, Brandt S, Blaese RM. Fibrosarcoma cells transduced with the IL-6 gene exhibit reduced tumorigenicity, increased immunogenicity, and decreased metastatic potential. Cancer Res 52:6020–6024;1992.
Lasdorp PM, Aarden LA, Calafat J, Zeiljemaker WP. A growth-factor dependent B-cell hybridoma. Curr Top Microbiol Immunol 132:105–113;1986.
Imanishi K, Yamaguchi K, Honda S. Transforming growth factor-α as a possible autocrine growth factor for human adenocarcinoma of the lung. In: Imura H, Shizyme K, Yoshida S, eds. Progress in Endocrinology. Amsterdam, Elsevier, 1363–1368;1988.
Pelton RW, Moses HL. The beta-type transforming growth factor. Am Rev Respir Dis 142:S31-S35;1990.
Nakanishi Y, Mulshine JL, Kasprzyk PG, Natale RB, Maneckjee R, Avis I, Treston AM, Gazdar AF, Minna JD, Cuttitta F. Insulin-like growth factor-I can mediate autocrine proliferation of human small cell lung cancer lines in vitro. J Clin Invest 82:354–359;1988.
Levy Y, Tsapis A, Brouet JC. Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines. J Clin Invest 88:696–698;1991.
Lu C, Kerbel RS. Interleukin-6 undergoes transition from paracrine growth inhibitor to autocrine stimulator during human melanoma progression. J Cell Biol 120:1281–1288;1993.
Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 61:759–767;1990.
Author information
Authors and Affiliations
Additional information
They have contributed equally to this work.
Rights and permissions
About this article
Cite this article
Cho, DH., Kang, HS., Ma, JJ. et al. IL-6 undergoes transition from in vitro autocrine growth factor to in vivo growth inhibitor of B lymphoma cells. J Biomed Sci 4, 201–207 (1997). https://doi.org/10.1007/BF02253419
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02253419