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 n
onhematopoietic cells as well as some tumor cells. Unlike its mitogeni
c effect on B cells, IL-4 inhibits the growth of some cancer cells bl
vitro. In this study, we show that IL-4R is expressed by breast and ov
arian cancer cell lines. Furthermore, anchorage-dependent and -indepen
dent growth of breast cancer cell lines MCF-7 and MDA-MB-231 is inhibi
ted by IL-4 treatment, and this effect requires IL-4R. Interestingly,
IL-4 only inhibited proliferating breast cancer cells and had no effec
t on basal, unstimulated growth. We therefore characterized the effect
of IL-4 on breast cancer cell growth stimulated by either estradiol o
r insulin-like growth factor I (IGF-I). In both anchorage-dependent an
d -independent growth assays, IL-4 inhibited estradiol-stimulated grow
th, The antiestrogen effect of IL-4 was not due to IL-4 interference w
ith the estrogen receptor, because IL-4 did not interfere with estroge
n receptor-mediated reporter gene transactivation. In contrast, IL-4 h
ad 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 cleav
age of poly(ADP-ribose) polymerase; and (e) the presence of cells with
sub-G(1) DNA content. IL-4 increased the percentage of apoptotic cell
s in MCF-7 and MDA-MB-231 cells 6.0- and 6.7-fold over that of the con
trol, respectively. Finally, the addition of IGF-I reversed IL-4-induc
ed apoptosis, suggesting that the mechanism of IL-4-induced growth inh
ibition in human breast cancer cells is the induction of programmed ce
ll death.