Hormonal control of plasmin and tissue-type plasminogen activator activity in rat milk during involution of the mammary gland

Abstract

We have proposed that growth hormone (GH) and prolactin (PRL) interact to suppress apoptosis in the mammary gland. GH increases insulin-like growth factor-I (IGF-I) synthesis whereas PRL suppresses the production of insulin-like growth factor-binding protein-5 (IGFBP-5) in the epithelial cells, which would otherwise inhibit IGF-mediated cell survival. IGFBP-5 was present in milk from involuting glands at high concentrations (approximately 60 microg/ml) and had a high affinity (8.03 x 10(-10) M) for IGF-I, suggesting an inhibitory effect of IGFBP-5 in the mammary gland. IGFBP-5 was present in the micellar fraction of milk and binds specifically to alpha(s2)-casein. Since alpha(s2)-casein also binds plasminogen and tissue-type plasminogen activator (t-PA), resulting in the conversion of plasminogen to plasmin, and since IGFBP-5 binds to plasminogen activator inhibitor-1 (PAI-1), we investigated whether apoptosis and extracellular matrix (ECM) degradation might be coordinately controlled by GH and PRL possibly acting through IGFBP-5. Litters were removed from lactating rats to initiate involution. Plasminogen activation and t-PA activity were both increased dramatically after 48 h and GH and PRL suppressed this response. By contrast, 17beta-oestradiol, progesterone or corticosterone did not influence either process. An antiserum to IGF-I, which blocked systemic IGF-I effects, failed to inhibit the activation of plasminogen or the increase in t-PA, suggesting that paracrine effects of IGF-I may be more important. Teat-sealing, which led to the accumulation of milk without hormonal changes, also led to increases in plasminogen activation and t-PA activity, suggesting that locally produced factors (of which IGFBP-5 is one) are important in controlling ECM remodelling. We propose that GH and PRL inhibit apoptosis and ECM remodelling by a process that involves the control of IGF-I and PAI-1 availability by IGFBP-5, thus allowing these processes to be tightly coordinated.