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

We have proposed that growth hormone (GH) and prolactin (PRL) interact to s uppress apoptosis in the mammary gland. GH increases insulin-like growth fa ctor-I (IGF-I) synthesis whereas PRL suppresses the production of insulin-l ike growth factor-binding protein-5 (IGFBP-5) in the epithelial cells, whic h would otherwise inhibit IGF-mediated cell survival. IGFBP-5 was present i n milk from involuting glands at high concentrations (approximately 60 mug/ ml) and had a high affinity (803 x 10(-10) M) for IGF-I, suggesting an inhi bitory effect of IGFBP-5 in the mammary gland. IGFBP-5 was present in the m icellar fraction of milk and binds specifically to alpha (s2)-casein. Since u(s2)-casein also binds plasminogen and tissue-type plasminogen activator (t-PA), resulting in the conversion of plasminogen to plasmin, and since IG FBP-5 binds to plasminogen activator inhibitor-1 (PAI-1), we investigated w hether apoptosis and extracellular matrix (ECM) degradation might be coordi nately controlled by GH and PRL possibly acting through IGFBP-5. Litters were removed from lactating rats to initiate involution. Plasminoge n activation and t-PA activity were both increased dramatically after 48 h and GH and PRL suppressed this response. By contrast, 17 beta -oestradiol, progesterone or corticosterone did not influence either process. An antiser um to IGF-I, which blocked systemic IGF-I effects, failed to inhibit the ac tivation 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 accu mulation of milk without hormonal changes, also led to increases in plasmin ogen 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.