Novel neurotrophin-1/B-cell stimulating factor-3 (NNT-1/BSF-3) is a gp130 cytokine potently stimulating corticotroph POMC gene expression and ACTH secretion by a Jak-STAT dependent mechanism. In the current study, we examined the regulation of NNT-1/BSF-3 mRNA expression in murine pituitary folliculostellate TtT/GF cells using Northern blot technique. A 5- to 9-fold and a 4- to 7-fold induction in NNT-1/BSF-3 mRNA expression was observed between 2 and 6 h stimulation with the protein kinase C (PKC) stimulus PMA (100 nM) and the protein kinase A (PKA) stimulus Bu₂cAMP (5 mM), respectively. Pituitary adenylate cyclase-activating polypeptide (PACAP-38, 50 nM) and vasoactive-intestinal-peptide (VIP, 50 nM) also stimulated NNT-1/BSF-3 mRNA expression 5- to 9-fold between 2 and 6 h. Preincubation with PKC and PKA inhibitors such as H-7 (20 µM), GF109203 x (50 µM) and H-89 (50 µM) decreased the stimulatory effects of PACAP and VIP. Both PACAP-38 and VIP also rapidly induced ERK1/2 phosphorylation and their stimulatory effect on NNT-1/BSF-3 mRNA expression was reduced by the MEK inhibitor U0126 (10 µM). Dexamethasone (10^-7 M) was a potent inhibitor of PMA-induced NNT-1/BSF-3 expression. RT-PCR analysis demonstrated TtT/GF cells to express the PACAP and VIP receptors PAC1-R and VPAC2-R, whereas in contrast to normal pituitary, TtT/GF did not express the "hip"-splice variant of the PAC1-R. In summary, NNT-1/BSF-3 is expressed in pituitary folliculostellate TtT/GF cells and induced by PKC, PKA and ERK1/2 dependent mechanisms. The novel gp130 cytokine NNT-1/BSF-3 derived from folliculostellate cells, might act as a paracrine neuroimmunoendocrine modulator of pituitary corticotroph function.