Active and Total Transforming Growth Factor-β1 Are Differentially Regulated by Dopamine and Estradiol in the Pituitary

Dopamine, acting through the dopamine type 2 receptor (Drd2), is the main inhibitor of pituitary prolactin (PRL) secretion and lactotroph proliferation. TGF-beta 1 is involved, at least in part, in mediating these actions. It was described that TGF-beta 1 synthesis in rat pituitary lactotrophs is up-regulated by dopamine and down-regulated by estradiol. TGF-beta 1 is secreted as a large latent complex. The local regulation of cytokine activation in the pituitary has not yet been explored. In this work, we studied pituitary active and total TGF-beta 1 content, as well as TGF-beta 1 mRNA, and the in vivo role of dopamine and estradiol on pituitary TGF-beta 1 levels. Adult female mice (wild type), and female mice with a null mutation in the Drd2 (Drd2(-/-)), were used. The loss of dopaminergictone induced a decrease in TGF-beta 1 mRNA expression, in active and total cytokine content, and in TGF-beta type II receptor expression. Dopamine regulation of pituitary TGF-beta 1 activation process was inferred by the inhibition of active cytokine by in vivo sulpiride treatment. Interestingly, in the absence of dopaminergic tone, estradiol induced a strong increase in active TGF-beta 1. PRL secretion correlated with active, but not total cytokine. TGF-beta 1 inhibitory action on lactotroph proliferation and PRL secretion was decreased in Drd2(-/-) pituitary cells, in correlation with decreased TGF-beta type II receptor. The study of the TGF-beta 1 activation process and its regulation is essential to understand the cytokine activity. As an intermediary of dopamine inhibition of lactotroph function, TGF-beta 1 and local activators may be important targets in the treatment of dopamine agonist-resistant prolactinomas. (Endocrinology 152: 2722-2730, 2011)