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The multiple activities of IGF-I and -II are modulated by a family of IGF-binding proteins (IGFBP-1 to -6). Although structurally related, each IGFBP has unique properties and exerts specific functions. IGFBP-5 is the most conserved IGFBP across species and was identified as an essential regulator of physiological processes in bone, kidney and mammary gland. In addition, IGFBP-5 appears to play a decisive role in the control of proliferation of specific tumour cell types. In many situations IGFBP5 exerts biological activities in the absence of IGFs, indicating the existence of IGF-independent actions. This concept was supported by the unexpected localisation of IGFBP-5 in the nucleus and the description of IGFBP-5-specific membrane-bound IGFBP-5 receptor(s). The scope of this review is to summarise the available information about the structure of IGFBP-5 and the regulation of its expression. Furthermore, the potential significance of IGFBP-5 in the regulation of physiological processes will be critically analysed in the light of recent experimental data.
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IGFs have multiple functions regarding cellular growth, survival and differentiation under different physiological and pathological conditions. IGF effects are modulated systemically and locally by six high-affinity IGF-binding proteins (IGFBP-1 to -6). Despite their structural similarity, each IGFBP has unique properties and exhibits specific functions. IGFBP-4, the smallest IGFBP, exists in both non-glycosylated and N-glycosylated forms in all biological fluids. It is expressed by a wide range of cell types and tIssues, and its expression is regulated by different mechanisms in a cell type-specific manner. IGFBP-4 binds IGF-I and IGF-II with similar affinities and inhibits their actions under almost all in vitro and in vivo conditions. In this review, we summarize the available data regarding the following aspects of IGFBP-4: genomic organization, protein structure-function relationship, expression and its regulation, as well as IGF-dependent and -independent actions. The biological significance of IGFBP-4 for reproductive physiology, bone formation, renal pathophysiology and cancer is discussed.
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ABSTRACT
Discordant results on body fluid levels of human chorionic gonadotrophin (hCG) free α- and β-subunits under physiological and pathophysiological conditions, prompted us to raise a total of 260 monoclonal antibodies (MCA) against free hCG-α, free hCG-β, holo-hCG, human follicle-stimulating hormone and bovine luteinizing hormone; 153 MCA recognizing the human α-subunit and 28 reacting with hCG-β were extensively analysed for their intra- and interspecies cross-reactivity with homologous hormones, and for the compatibility of epitopes recognized by them. The immunological topography of free hCG-α and free hCG-β was resolved by these MCA, and epitope maps were designed. Six antigenic determinants on the free α-chain (α1–α6), clustered in three spatially distinct domains, and seven epitopes on the surface of free hCG-β (β1–β7), could be distinguished. Strikingly, three α-chain epitopes (α4, α5 and α6) were shared between various species, which is in contradiction to the concept of immunological species-specificity of α-subunits. Three determinants were found to be present only on the free subunits but not on holo-hCG (α6, β6 and β7), and only two determinants (β1 and β7) were hormone-specific for hCG. Based on this information, an immunoenzymometric assay for the free α-subunit of human glycoprotein hormones was established, with a sensitivity of 1·3 pg/well and a cross-reactivity with holo-hCG of less than 0·005% Thus this assay provides the basis for detecting free α-subunits in the presence of extremely high levels of holo-hormones, which may assist in elucidating the role of free α-subunits in man.
Journal of Endocrinology (1990) 125, 301–309
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ABSTRACT
Patients who had been included in a randomized double-blind placebo-controlled trial on the efficacy of cyclosporin A (CyA) in producing remissions in insulin-dependent diabetes mellitus (IDDM) type I were investigated for humoral and cellular immunologic parameters. Whereas metabolic derangement before the initiation of insulin treatment led to small but significant decreases in the percentage of CD4-positive lymphocytes as well as of the activity of natural killer (NK) cells and antibody-dependent cellular cytotoxicity (ADCC), the administration of CyA did not influence any of the immunologic parameters tested, which included proliferative lymphocyte responses to mitogens and alloantigens and serum concentrations of immunoglobulins G, A and M. Thus NK cell activity, ADCC as well as the percentage of CD4-positive lymphocytes returned to normal levels in parallel with the normalization of glycosylated haemoglobin (HbAlc), but were not further influenced in their course by the administration of CyA, as compared with patients receiving placebo. Interferon-induced augmentation of NK cell activity did not differ between patients with IDDM on placebo and those under CyA therapy. All other investigated parameters also remained unchanged during the time of CyA therapy. We conclude that metabolic derangement leads to a reversible disturbance of certain cellular immune functions, but their normalization achieved by insulin treatment and their further course remains uninfluenced by the administration of CyA.
Journal of Endocrinology (1989) 121, 177–183
Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Institute of Veterinary Biochemistry, Free University of Berlin, Oertzenweg 19b, D-14163 Berlin, Germany
Institute of Molecular Animal Breeding and Biotechnology, Gene Centre of the Ludwig-Maximilians-University Munich, Munich, Germany
Institute of Veterinary Anatomy, Histology and Embryology, Ludwig-Maximilians-University Munich, Veterinaerstr. 13, 80539 Munich, Germany
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Nitric oxide synthases (NOS) account for the endogenous production of nitric oxide (NO), a small and permeable bioreactive molecule. NO is known to act as a paracrine mediator during various processes associated with female reproduction. In the present study, the mRNA expression of the endothelial (eNOS) and inducible (iNOS) NO synthases were examined in bovine oviduct epithelial cells (BOEC) during the oestrous cycle. In addition, eNOS and iNOS mRNA and protein were localised by in situ hybridisation and immunocytochemistry respectively. Furthermore, the effects of exogenously applied oestradiol-17β and progesterone on NOS mRNA regulation were studied in a suspension culture of BOEC. The eNOS mRNA abundance was low around ovulation (day 0) and increased significantly until pro-oestrus (day 18) in the ampulla. Immunoreactive protein of eNOS was detected predominantly in endothelial cells as well as in secretory oviduct epithelial cells at pro-oestrus. The iNOS mRNA concentration was significantly reduced in the isthmus at pro-oestrus (day 18) and oestrus (day 0) compared with persistently high levels in the ampulla. By in situ hybridisation, specific iNOS transcripts were additionally demonstrated in the oviduct epithelium. Immunoreactive iNOS protein was localised in secretory epithelial cells as well as in the lamina muscularis. The in vitro stimulation showed that both NOS were stimulated by progesterone, but not by oestradiol-17β. The region-specific modulated expression of eNOS and iNOS provides evidence for an involvement of endogenously produced NO in the regulation of oviductal functions.
