PITUITARY FOLLICULO-STELLATE-LIKE CELL-LINE (TTT GF) RESPONDS TO NOVEL HYPOPHYSIOTROPIC PEPTIDE (PITUITARY ADENYLATE CYCLASE-ACTIVATING PEPTIDE), SHOWING INCREASED ADENOSINE-3',5'-MONOPHOSPHATE AND INTERLEUKIN-6 SECRETION AND CELL-PROLIFERATION

Several studies have shown that folliculo-stellate cells (FS cells) in the anterior pituitary gland exhibit paracrine functions. Recently, we established a pituitary FS-like cell line, TtT/GF, which was derived from an isologously transplantable pituitary thyrotropic tumor line induced by radiothyroidectomy. In studies to examine the function of FS cells, we found that two forms of a novel hypophysiotropic peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), were potent activators of TtT/GF cells. Both the 27- and 38-amino acid forms of PACAP (PACAP-27 and PACAP-38) and vasoactive intestinal peptide (VIP) increased the levels of cAMP in TtT/GF cells in a similar dose-dependent manner. PACAP-27 and PACAP-38 specifically stimulated the proliferation of TtT/GF cells dose dependently, whereas VIP was ineffective. The minimal effective concentration of the PACAPs inducing cell proliferation was between 10(-8)-10(-7) m. However, PACAP-27 was much less potent than PACAP-38 in stimulating cell proliferation and DNA synthesis. PACAP-38, PACAP-27, and VIP all stimulated the release of interleukin-6 (IL-6) from TtT/GF cells. PACAP 38 (10-8 m) stimulated IL-6 production effectively within 1 h of incubation, and the level attained at 8 h of cultivation (620 pg/ml) was nearly 10-fold that in the absence of PACAP-38 (60 pg/ml). PACAP-38 and VIP stimulated IL-6 secretion significantly at 10(-10)-10(-9) m in a bell-shaped manner; the maximum values were 10(-7) and 10(-8) M, respectively. On the other hand, IL-6 secretion stimulated by PACAP-27 became saturated at 10(-8) m, and the maximum value (320 pg/ml) was about 25% of that stimulated by PACAP-38 (1280 pg/ml). These findings obtained using TtT/GF cells as a model of FS cells suggest that PACAP acts as a hypophysiotropic factor, which targets FS cells and stimulates their proliferation, adenylate cyclase activation, and IL-6 secretion.