title: 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.
authors.affiliation: Hannah Research Institute, Ayr KA6 5HL.
authors.forename: E
authors.initials: E
authors.lastname: Tonner
authors.forename: G J
authors.initials: GJ
authors.lastname: Allan
authors.forename: D J
authors.initials: DJ
authors.lastname: Flint
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D017886:Durapatite / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005341:Fibrinolysin / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology / Q000502:physiology*; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007774:Lactation / Q000502:physiology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D008892:Milk / Q000378:metabolism*; D008894:Milk Proteins / Q000378:metabolism; D010958:Plasminogen / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D014461:Ultracentrifugation
chemical_list: D006728:Hormones; D018975:Insulin-Like Growth Factor Binding Protein 5; D008894:Milk Proteins; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D010958:Plasminogen; D017886:Durapatite; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin