Differential Effect of Age on Transforming Growth Factor- 1 Inhibition of Prolactin Gene Expression Versus Secretion in Rat Anterior Pituitary Cells

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Abstract
Transforming growth factor-b1 (TGF-b1) synthesized in the pitu- itary may act as an autocrine/paracrine regulator of lactotrope func- tion. We examined the effects of TGF-b1 on PRL messenger RNA (mRNA), PRL synthesis, and PRL secretion in cultured anterior pi- tuitary (AP) cells from rats at different ages. APs excised from ovari- ectomizedfemaleSprague-Dawleyrats,eitheryoung(2-3monthsold; average serum PRL: 9 ng/ml), middle-aged (11-12 months old; aver- age serum PRL: 133 ng/ml), or old (24 months old; average serum PRL: 159 ng/ml), were dispersed and cultured for 5 days. Then, cells were washed and challenged with increasing doses of TGF-b1 (0-100 ng/ml) for 1-48 h in serum-free medium. Northern blot analysis showed an increase in basal PRL mRNA levels, and a decrease in responsiveness to TGF-b1 with age. TGF-b1 suppressed PRL mRNA in a dose- and time-dependent manner in cells from young rats. Max- imum inhibition was observed at 0.5-1 ng/ml of TGF-b1. At 0.5 ng/ml TGF-b1, significant reduction in PRL mRNA was detected at 6 h, and maximum inhibition was observed at 12-48 h post TGF-b1 incuba- tion. Cells from middle-aged rats were less responsive to TGF-b1, whereas cells from old rats did not seem to respond under our ex- perimentalconditions.InadditiontoitseffectonPRLmRNAinyoung AP cells, TGF-b1 dose dependently inhibited the rate of PRL syn- thesis, as indicated by reduced (35S)methionine incorporation into immunoprecipitated PRL. Responsiveness of PRL synthesis to TGF-b1 inhibition also decreased with age; however, significant in- hibition by TGF-b1 on PRL synthesis could still be observed in old AP cells. Analysis by RIA demonstrated that young AP cells produced lower levels (15 mg/106 cellsz24 h) of PRL in culture medium than old AP cells (32 mg/106cellsz24 h). TGF-b1 decreased medium PRL levels in old AP cells as efficaciously as in young AP cells. Significant re- duction in medium PRL secreted by young AP cells was observed at 3 h when changes in both PRL mRNA and PRL synthesis were not evident. Taken together, our data suggest that TGF-b1 affects PRL production at multiple levels. Moreover, its inhibition on PRL syn- thesisandmRNAexpression,butnotonPRLsecretion,isage-related. Thus, TGF-b1 may play an important role in regulating lactotrope function during aging. (Endocrinology 138: 878-885, 1997)

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