“ TGFb1 IN A PROLACTINOMA EXPERIMENTAL MODEL: THE DOPAMINE RECEPTOR D2 KNOCK OUT MICE (Drd2-/-)”

RECOUVREUX MV; GUIDA MC; BECU-VILLALOBOS D; DÍAZ G

San Diego, CA, USA

Congreso; Endo 2010; 2010

The Endocrine Society

Prolactinomas are the most frequent  pituitary tumors. Dopamine type 2 receptor (Drd2) mediates dopamine inhibition of prolactin on lactottropes. Therefore, female Drd2-/- micce develop prolactinomas, chronic hyperprolactinemia and lactotrope hyperplasia. TGFb1 is a potent cytokine that regulates many biological functions such as growth and apoptosis in various cell types. TGFb1 must undergo a highly regulated activation process to be functional. Activation consists in dissociation of the cytokine from its large latent comple that sequesters and attaches it to the extracellular matrix. TGFb1 is locally synthesized by lactotropes where it inhibits cell proliferation and prolactin synthesis. It was suggested that TGFb1 might mediate, in part, dopamine inhibitory action on lactotrope cells in rats. On this basis, the aim of this study was to evaluate total and active TGFb1 and its regulation by dopamine and estradioll, in pituitary glands from Drd2-/- and wild-type (wt) mice. Active or total TGFb1 content in pituitary homogenates was quantified by ELISA with a TGFb1 Emax ImmunoAssay-System (PROMEGA). Significantly lower pituitary active TGFb1 was found in both male and female Drd2-/- mice when compared with wt mice (p<0.0001). Females of both genotypes showed lower active TGFb1 levels than males (p=0.0003). However, we did not find significant differences in total pituitary TGFb1 between genotype o sex. On the other hand, we found that ip sulpiride (10mg/kg, 24hs) lowered active pituitary TGFb1 in wt females but not in males (p=0.01), although it increased serum prolactin levels in both sexes. Cabergoline treatment (2mg/kg, 24hs) did ot affect active pituitary TGFb1 content in either sex, in spite of its lowering effect on serum prolactin. Surprisingly, estradiol treatment (0.2mg/kg, sc. 24hs) increased active TGFb1 in Drd2-/- pituitaries from female mice (p=0.013), without affecting total TGFb1 in either sex or genotype. In summary, we demonstrate that active but not total pituitary TGFb1 content is reduced by disruption of the Drd2. Our results suggest a dopaminergic and estrogenic control on cytokine activation process at the pituitary level. We also found a sexually differentiated dopaminergic and estrogenic control on pituitary active TGFb1 expression. The lower active TGFb1 in Drd2-/- pituitaries could contribute to prolactinoma development, positioning TGFb1 as a possible target for therapeutic treatment.