Insulin-Like Growth Factor II (IGF-II) Is More Potent Than IGF-I in Stimulating Cortisol Secretion from Cultured Bovine Adrenocortical Cells: Interaction with the IGF-I Receptor and IGF-Binding Proteins

Although the stimulating effect of insulin-like growth factor I
(IGF-I) on adrenal steroidogenesis has been well established, the
role of IGF-II in the adult adrenal gland remains unknown. We,
therefore, investigated the effect of recombinant human IGF-II on
cortisol and cAMP synthesis from adult bovine adrenocortical cells.
IGF-II, time and dose dependently, stimulated basal cortisol
secretion maximally 3-fold. In combination with ACTH, IGF-II (13
nM) synergistically increased cortisol secretion from 1-fold
(10(-8) M ACTH) to 28-fold of untreated control levels. In
contrast, IGF-I at equimolar concentrations did not show an effect
on basal cortisol secretion, and in combination with ACTH elicited
a significant weaker stimulatory effect than IGF-II (22-fold
increase). The synergistic effect of IGF-II on ACTH-promoted
cortisol secretion was paralleled by accumulation of cAMP in the
culture medium. Although both IGF receptors are present in adult
bovine adrenocortical cells, the effect of IGF-II seems to be
mediated through interaction with the IGF-I receptor, as
[Arg54,55]IGF-II, which only binds to the IGF-I receptor, was
equipotent to native IGF-II, whereas [Leu27]IGF-II, which
preferentially binds to the type II IGF receptor, did not show any
effect. By Western ligand blotting, four different molecular forms
of IGF-binding proteins (IGFBPs) were identified in conditioned
medium of bovine adrenocortical cells with apparent molecular
masses of 39-44, 34, 29, and 24 kilodaltons. ACTH treatment
increased the abundance of all binding proteins, on the average,
2.3-fold, except for the 29-kDa band, which was predominantly
induced 6.8-fold. Additionally, [des1-3]IGF-I, a truncated IGF
variant that exhibits only minimal binding to IGFBPs, was
significant more potent than IGF-I and elicited the same maximum
stimulatory effect on cortisol secretion as IGF-II and
[des1-6]IGF-II. In conclusion, these results demonstrate that 1)
IGF-II stimulates basal as well as ACTH-induced cortisol secretion
from bovine adrenocortical cells more potently than IGF-I; 2) this
effect is mediated through interaction of IGF-II with the IGF-I
receptor; 3) bovine adrenocortical cells synthesize various IGFBPs
that are induced differentially by ACTH; and 4) IGFBPs apparently
play a modulatory role in IGF-induced stimulation of adrenal
steroidogenesis. Therefore, bovine adult adrenocortical cells
provide a useful tissue culture model in which the interactions
among locally produced IGFs, IGFBPs, and the IGF-I receptor can be
evaluated.