Interleukin 4 inhibits growth and induces apoptosis in human breast cancer cells.
Interleukin-4 (IL-4) is a pleiotropic cytokine produced by mast cells and T lymphocytes that promotes proliferation and immunoglobulin class-switching in B cells. IL-4 receptors (IL-4Rs) are also expressed by nonhematopoietic cells as well as some tumor cells. Unlike its mitogenic effect on B cells, IL-4 inhibits the growth of some cancer cells in vitro. In this study, we show that IL-4R is expressed by breast and ovarian cancer cell lines. Furthermore, anchorage-dependent and -independent growth of breast cancer cell lines MCF-7 and MDA-MB-231 is inhibited by IL-4 treatment, and this effect requires IL-4R. Interestingly, IL-4 only inhibited proliferating breast cancer cells and had no effect on basal, unstimulated growth. We therefore characterized the effect of IL-4 on breast cancer cell growth stimulated by either estradiol or insulin-like growth factor I (IGF-I). In both anchorage-dependent and -independent growth assays, IL-4 inhibited estradiol-stimulated growth. The antiestrogen effect of IL-4 was not due to IL-4 interference with the estrogen receptor, because IL-4 did not interfere with estrogen receptor-mediated reporter gene transactivation. In contrast, IL-4 had no effect on IGF-I-stimulated proliferation. Because IGF-I is known to inhibit programmed cell death, we examined apoptosis as a possible mechanism of IL-4 action. We established that IL-4 induced apoptosis in breast cancer cells by five independent criteria: (a) morphological indicators including pyknotic nuclei and cytoplasmic condensation; (b) DNA fragmentation; (c) the formation of DNA laddering; (d) the cleavage of poly(ADP-ribose) polymerase; and (e) the presence of cells with sub-G1 DNA content. IL-4 increased the percentage of apoptotic cells in MCF-7 and MDA-MB-231 cells 6.0- and 6.7-fold over that of the control, respectively. Finally, the addition of IGF-I reversed IL-4-induced apoptosis, suggesting that the mechanism of IL-4-induced growth inhibition in human breast cancer cells is the induction of programmed cell death.
Gooch
J L
JL
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7884, USA.
Lee
A V
AV
Yee
D
D
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism*; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
D000972:Antineoplastic Agents, Phytogenic; D011960:Receptors, Estrogen; D019948:Receptors, Interleukin-4; D015847:Interleukin-4; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D017239:Paclitaxel