Abstract
IL-4 is a pleiotropic cytokine produced by T lymphocytes which acts on various cells of such as T and B lymphocytes, monocytes, fibroblast, endothelial cells, macrophages and some others. IL-4 was originary described as a B cell growth factor, and now known to provide potent anti-tumor activity against various tumors, including breast cancer. IL-4 can induce apoptosis in cultured breast cancer cells. In addtion, it has been clarified that IL-4 plays an important role in the regulation of estrogen synthesis enzymes including 17 β-HSD and 3 β-HSD. These findings imply that IL-4 is a key enzyme not only for Th2 type immune reactions but also for tumor cell growth itself in human breast cancer.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- IL:
-
Interleukin
- TNF:
-
Tumor necrosis factor
- IFN:
-
Interferon
- TCR:
-
T cell receptor
- TGF:
-
Transforming growth factor
- IGF:
-
Insulin-like growth factor
- IRS:
-
Insulin receptor substrate
- ICAM:
-
Intercellular adhesion molecule
- VCAM:
-
Vascular cell adhesion molecule
- ELAM:
-
E-selectin
- VEGF:
-
Vascular endothelial cell growth factor
- HSD:
-
Hydroxysteroid dehydrogenase
Reference
Howad M, Farrar J, Hilfiker M,et al: Identification of a T cell-derived B cell stimulatory factor distinct from IL-2.J Exp Med 155:914–923, 1982.
Yokota T, Arai N, de Vries J,et al: Molecular biology of interleukin-4 and interleukin-5 genes and biology of their products that stimulate B cells, T cells and haematopoietic cells.Immuno Rev 102:137–138, 1988.
Coffman RL, Seymour B, Lebman DA,et al: The role of helper T cell products in mouse B cell differentiation and isorype regulation.Immuno Rev 102:5–28, 1988.
Snpper CM, Finkelman FD, Paul WE: Regulation of IgG1 and IgE production by interleukin 4.Immunol Rev 102:29–56, 1988.
Noma Y, Sidras P, Naito T,et al: Cloning for cDNA encoding the murine IgG 1 induction factor by a novel strategy using SP6 promoter.Nature 319:640–644, 1986.
Mosmann TR, Coffman RL: TH1 and TH2 cells: difference patterns of lymphokine secretion lead to different functional properties.Ann Rev Immmunol 7:145–173, 1989.
Paliard X, De Waal MR, Yssel H,et al: Simultaneous production of IL-2, IL-4 and IFN-gamma by activated human CD + and CD+T cell clones.J Immunol 141:849–855, 1988.
Lewis DB, Prickett KS, Larsen Aet al: Restricted production of interleukin-4 by activated human T cells.Proc Natl Acad Sci USA 85:9743–9747, 1988.
van der Heijden FL, Wierenga EA, Bos JD,et al: High frequency of IL-4 producing CD4+allergen-specific T lymphocytes in atopic dermatitis lesional skin.J Invest Dermatol 97:389–394, 1991.
Banchereau J: Interleukin 4.Nucl Med Biol 17:619–623, 1990.
Lownthal JW, Castle BE, Christiansen J,et al: Expression of high affinity receptors for murine interleukin 4(BSF-1) on haematopoietic and non-haematopoietic cells.J Immunol 140:456–464, 1988.
Park LS, Friend D, Sassenfeld HM,et al: Characterization of the high affinity cell surface receptor for murine B cell stimulatory factor-1.Proc Natl Acad Sci USA 84:1669–1673, 1987.
Cabrillat H, Galizzi JP, Djossou O,et al: High affinity binding of human interleukin 4 to cell lines.Biochem Biophys Res Commun. 149:995–1001, 1987.
Idzerda RL, March CJ, Mosley B,et al: Human interleukin 4 receptor confers biological responsiveness and defines a novel receptor superfamily.J Exp Med 171:861–873, 1990.
Galizzi J-P, Zuber CE, Harada N,et al: Molecular cloning of a cDNA encoding the human IL-4 receptor.Int Immunol 2:669–675, 1990.
Bazan JF: A novel family of growth factor receptors: a common binding domain in the growth hormone, prolactin, erythropoietin and IL-6 receptors and the p75IL-2 receptor beta-chain.Biochemical and Bilphys Res Commun. 164:788–795, 1989.
Topp MS, Koenigsmann M, Anthony M,et al: Recombinant human interleukin-4 inhibits growth of some human lung tumor cell lines in vitro and in vivo.Blood 82:2837–2844, 1993.
Obiri NI, Siegel JP, Varricchio F,et al: Expression of high-affinity IL-4 receptors on human melanoma, ovarian and breast carcinoma cells.Clin Exp Immunol 85:148–155, 1994.
Obiri NI, Hillman GG, Haas GP,et al: Expression of high-affinity interleukin-4 receptors on human renal cell carcinoma cells and inhibition of tumor cell growth in vitro by interleukin-4.J Clin Invest 91:88–93, 1993.
Varricchio F, Obiri NI, Haas GP,et al: Immuno-staining of interleukin-4 receptors on human renal cell carcinoma.Lympyokine Cytokine Res 12:465–469, 1993.
Toi M, Bicknell R, Harris AL: Inhibition of colon and breast carcinoma cell growth by interleukin-4.Cancer Res 52:275–279, 1992.
Mat I, Larche M, Melcher D: Tumor associated upregulation of IL-4 receptor complex.Br J Cancer. 62 (supple x): 96–98, 1990.
Kaklamanis L, Koukourakis MI, Leek R: Loss of interleukin-4 receptor-associated molecule gp200-MR6 in human breast cancer; Prognostic significance.Br J Cancer 74:1627–1631, 1996.
Tubly A, Luqmani YA, Shousha S,et al: Differential expression of gp200-MR6 molecule in benign hyperplasia and down-regulation in invasive carcinoma of the breast.Br J Cancer 74:1005–1011, 1996.
Jung T, Bews JP, Enssle KH,et al: Detection of and discrimination between total and free human interleukin 4 and free soluble interleukin 4 receptor by EUSA.J Immunol Method 217:41–50, 1998.
Jung T, Wagner K, Neumann C,et al: Enhancement of human IL-4 activity by soluble IL-4 receptorsin vitro.Eur J immnol 29:864–871, 1999.
Jung T, Schrader N, Hellwing M,et al: Soluble human interleukin 4 receptor is produced by activated T cells under the control of metalloproteinases.Int Arch Allergy Immunol 119:23–30, 1999.
Zlotnick A, Ransom J, Frank G,et al: Interleukin 4 is a growth factor for activated thymocytes: Possible role in T cell ontogeny.Proc Natl Acad Sci USA 84:3856–3860, 1987.
Spits H, Yssel H, Paliard X,et al: IL-4 inhibits IL-2 mediated induction of human lymphokine-activated killer cells, but not the generation of antigen specific cytotoxic T lymhocytes in mixed lymphocyte cultures.J Immunol 141:29–36, 1988.
Brown M, Hu-Li J, Paul WE: IL-4/B cell stimulatory factor-1 stimulates T cell growth by an IL-2 independent mechanism.J Immunol 141:504–511, 1988.
Widmer MB, Grabstein KH: Regulation of cytolytic T lymphocytes generation by B cell stimulatory factors.Nature 326:795–798, 1987.
Lee F, Yokota T, Otsuka T,et al: Isolation and characterization of a mouse interleukin cDNA clone that express B-cell stimulatory factor 1 activities and T-cell and mast-cell stimulating activities.Proc Natl Acad Sci USA 83:2061–2065, 1986.
Paul WE, Ohara J: B-cell stimulatory factor-1/interleukin 4.Ann Rev Immunol 5:429–459, 1987.
Santin AD, Ioli GR, Hiserodt JC,et al: Development and characterization of an IL-4 secreting human ovarian carcinoma cell line.Gynecol Oncol 58:230–239, 1995.
Golumbek PT, Lazenby AJ, Levitsky HI,et al: Treatment of established renal cancer by tumor cells engineered to secrete interleukin 4.Science 254:713–716, 1991.
Tepper RI, Pittengale PK, Leder P: Murine interleukin4 displays potent anti-tumor activityin vivo.Cell 57:503–512, 1989.
Blais Y, Gingras S, Haagensen DE,et al: Interleukin-4 interlelukin-13 inhibit estrogen-induced breast cancer cell proliferation and stimulate GCDFP-15 expression in human breast cancer cells.Mol Cell Endocrinol 121:11–18, 1996.
Topp MS, Papadimitriou CA, Eitelbach F,et al: Recombinant human interleukin 4 has antiproliferative activity on human tumor cell lines derived from epithelial and nonepithelial histologies.Cancer Res, 55:2173–2176, 1995.
Cressent M, Pidoux E, Cohen R,et al: Interleukin-2 and interleukin-4 display potent antitumor activity on rat medullary thyroid carcinoma cells.Euro J Cancer 31A:2379–2384, 1995.
Klara T, Bharat BA: Interleukin4 potentiates the antiproliferative effect of tumor necrosis factor on various tumor cell lines.Cancer Res 51:4266–4270, 1991.
Gooch JL, Lee AV, Yee D: Interleukin4 inhibit growth and induce apoptosis in human breast cancer cells.Cancer Res 58:4199–4205, 1998.
Blais Y, Zhao C, Huber M,et al: Growth-independent induction of spermidine transport by IL-4 and IL-13 in human cancer cells.Int J Cancer 67:532–538, 1996.
Pericle F, Giovarelli M, Colombo MP: An efficient Th2-type memory follows CD8 + lymphocyte-deriven and eosinophil-mediated rejection of a spontaneous mammary adenocarcinoma engineered to release IL-4.J Immunol 153:5659–5673, 1994.
Allione A, Consalvo M, Nanni P,et al: Immunizing and curative potential of replicating and nonreplicating murine mammary adenocarcinoma cells engineered with IL-2, IL-4, IL6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, and gamma-interferon gene or admixed with conventional adjuvants.Cancer Res 54:6022–6026, 1994.
Musiani P, Allione A, Modica A,et al: Role of neutrophils and lymphocytes in inhibition of a mouse mammary adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL10. IFN-alpha, IFN-gamma, and TNF-alpha.Lab Inves 74:146–157, 1996.
Maeda T, Matsubara H, Sugaya M: Loss of tumorigenecity of human breast cancer cells engineer to produce IL-2, IL-4 or GM-CSF in nude mice.Int J Oncol 15:943–7, 1999.
Pacor S, Gagliardi R, Spessotto P: Paracrine effects of IL-4 transfection on TS/A adenocarcinoma cells mediate reduced in vivo growth.Pathol Oncol Res 5:110–16, 1999.
Butcher EC: Leukocyte-endothelial cell recognition: three or more steps to specificity and diversity.Cell 67:1033–1036, 1991.
Schleimer RP, Sterbinsky SA, Kaiser J,et al: IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium.J Immunol 148:1086–1092, 1992.
Volpert OV, Fong T, Koch AE,et al: Inhibition of angiogenesis by interleukin 4.J Exp Med 188:1039–1046, 1998.
Saleh M, Davis ID, Wilks AF: The paracrine role of tumor-derived mIL-4 on tumor-associated endo-thelium.Int J Cancer 72:664–672, 1997.
Turgeon C, Gingras S, Carriere MC,et al: Regulation of sex steroid formation by interleukin 4 and interleukin 6 in breast cancer cells.J Steroid Mole Biol 65:151–162, 1998.
Gingras S, Moriggl R, Groner B,et al: Induction of 3 β -hydroxysteroid dehydrogenase/delta5-delta4 isomerase type 1 gene transcription in human breast cancer cell lines and in normal mammary epithelial cells by interleukin-4 and inerleukin-13.Mol Endocrinol 13:66–81, 1999.
Whitehead RP, Unger JM, Goodwin JW,et al: Phase II trial of recombinant human inteleukin 4 in patients with disseminated malignant melnoma; A South west Oncology Group study.J Immunol 21:440–446, 1998.
Vokes EE, Figlin R, Hochster H: A phase II study of recombinant human interleukin 4 for advanced or recurrent non-small cell lung cancer.Cancer J Sci Am 4:46–51, 1998.
Stadler WM, Rybak ME, Vogelzang NJ: A phase II study of subcutaneous recombinant human interleukin 4 in metastatic renal cell carcinoma.Cancer 76:1629–1633, 1995.
Margolin K, Aronson FR, Sznol M,et al: Phase II studies of recombinant human interleukin 4 in advanced renal cancer and malignant melanoma.J Immunolther Emphasis Tumor Immunol 15:147–53, 1994.
Author information
Authors and Affiliations
About this article
Cite this article
Nagai, S., Toi, M. Interleukin-4 and breast cancer. Breast Cancer 7, 181–186 (2000). https://doi.org/10.1007/BF02967457
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02967457