Prolactin and growth hormone signal transduction in lymphohaemopoietic cells

The peptide hormones, prolactin (PRL) and growth hormone (GH), are known to regulate numerous target tissues. Among such targets are cells of the immune system, including T cells, B cells, macrophages and natural killer cells. We have cloned a panel of PRL- and GH-inducible T cell genes for use in studies to understand how these hormones through the expression of these genes modulate the biology of immune function cells. This article focuses on the signalling pathways emanating from the PRL receptor (PRL-R) and GH receptor (GH-R), and the expression of PRL-inducible target genes.     

The role of growth hormone and insulin-like growth factors in the immune system

Growth hormone (GH) and insulin-like growth factor I (IGF-I) can modulate the development and function of the immune system. In this chapter, we present data on the expression of receptors for GH and IGFs and the in vitro and in vivo effects of these proteins. We show that expression of GH and IGFs in the immune system opens up the possibility that these proteins are not only involved in endocrine control of the immune system but can also play a role as local growth and differentiation factors (cytokines). Endocrine control of GH could be direct or mediated via endocrine or autocrine/paracrine IGF-I. In addition, GH can act as an autocrine or paracrine factor itself. Furthermore, IGF-I in the immune system has been shown to be regulated by cytokines, such as interleukin-1 and interferon-γ, alluding to a cytokine-like function of IGF-I. In addition to data on the function of GH and IGF-I in the immune system, we present new findings which imply a possible function of IGF-II and IGF-binding proteins.     

Somatic growth in hypophysectomized pituitary-homografted rats is promoted by prolactin

Summary Hypophysectomized male rats bearing a homograft of two adenopituitaries under the kidney capsule showed a significant increase in b.wt as compared to hypophysectomized non-homografted animals. Radiommunoassay of growth hormone (GH), ACTH, -MSH,-endorphin and prolactin (PRL) revealed that only the latter was highly increased in the plasma of hypophysectomized homografted rats. These animals showed also increased levels of plasma corticosterone. However, daily injection of corticosterone failed to promote somatic growth in hypophysectomized non-homografted rats. These results suggest that PRL, and not other hormonal factors, promotes somatic growth in hypophysectomized homografted rats, and stress the concept that only PRL is secreted in significant amounts by pituitary homografts.     

Influence of somatostatin on serum prolactin concentrations of cows during rest and milking

Administration of somatostatin (SRIF) to lactating cows significantly increased basal, premilking serum concentrations of prolactin (PRL), and potentiated PRL release in response to milking and significantly reduced resting concentrations of growth hormone (GH).     

Influence of somatostatin on serum prolactin concentrations of cows during rest and milking

Summary Administration of somatostatin (SRIF) to lactating cows significantly increased basal, premilking serum concentrations of prolactin (PRL), and potentiated PRL release in response to milking and significantly reduced resting concentrations of growth hormone (GH).The author wishes to thank Ayerst Laboratories of Canada for donating the somatostatin for these studies.     

Prolactin and growth hormone releasing activity of [D-Met2, Pro5]-enkephalinamide in the rat after systemic administration

Summary The growth hormone (GH) and prolactin releasing (PRL) activity of [D-Met², Pro⁵]-enkephalinamide (EKNH₂), an opioid peptide analog with higher opiate agonist activity that morphine, was compared in the unanesthetized male rat to those of equimolar doses of morphine upon systemic injection. EKNH₂ proved to be a higher PRL, but not GH, releaser than the opiate alkaloid.     

Effect of apomorphine hydrochloride administration on serum concentrations of prolactin,and growth hormone in cattle

Summary Administration of apomorphine hydrochloride to cattle significantly depressed serum prolactin (PRL) concentrations and elevated serum growth hormone (GH) concentrations in a dosimetric fashion.     

Somatostatin immunoneutralization overcomes the inhibitory effects of quipazine and pargyline on growth hormone secretion in domestic fowl

Summary The inhibitory effects of pargyline and quipazine on chicken growth hormone secretion were overcome by passive immunoneutralization of endogenous somatostatin (SRIF)-14 or SRIF-28(1–14)-like immunoreactivity. Administration of the specific antisera to control birds pretreated with 0.9% NaCl elevated the basal plasma GH concentrations. These results suggest that peptides with SRIF-14 or SRIF-28(1–14)-like immunoreactivity tonically inhibit GH secretion and are at least partially responsible for the inhibitory effects of pargyline and quipazine on GH release in immature domestic fowl.     

Thyrotropin-releasing hormone does not inhibit lysine vasopressin-induced growth hormone secretion in normal men

Summary In order to establish whether thyrotropin-releasing hormone (TRH) inhibits lysine-vasopressin (LVP)-induced growth hormone (GH) release, six normal men were tested with LVP alone or in combination with TRH. LVP strikingly increased serum GH levels; this response was not altered by TRH. These results indicated that in man TRH is not involved in the control of GH secretion in response to LVP.     

Studies on the thyroid in transgenic mice expressing the genes for human and bovine growth hormone

Summary The thyroid glands of transgenic mice (TM) expressing the genes for human (h) and bovine (b) growth hormone (GH) were studied. The percentages of larger follicles inhGH TM of either sex were significantly greater than in the corresponding normal littermates, and follicles ranging up to 350 m in diameter were present in malehGH TM. In contrast, thyroid follicles were only slightly enlarged in malebGH TM, and were unchanged in femalebGH TM. The serum concentrations of T4 were significantly decreased in malebGH TM and not altered in the other groups. Serum concentrations of T3 were slightly, but significantly increased in femalehGH TM and femalebGH TM, but were unaffected in male TM of either type. Since the principal difference between these foreign GHs in rodents is the additional lactogenic activity of human GH, these results may indicate that the effects of prolactin can influence the development of the thyroid.     

Regulation of B and T cell development by anterior pituitary hormones

Hormones produced by the anterior pituitary gland have been implicated in the regulation of primary lymphocyte development. In order to identify endocrine factors involved in that process, several strains of mice with genetic defects resulting in a selective impairment in the production of one or more anterior pituitary-derived hormones have been analysed. This study has resulted in the classification of endocrine hormones into the following four categories (i) hormones such as prolactin with no apparent effects on primary lymphopoiesis; (ii) anabolic hormones such as growth hormone and insulin-like growth factor-I whose stimulatory effects on primary lymphopoiesis are non-lineage-specific and related to their actions as systemic mediators of growth and/or differentiation; (iii) hormones such as thyroid hormones that have an obligate role in primary B lymphopoiesis; and (iv) hormones such as oestrogens that act as negative regulators of lymphopoiesis.     

Growth hormone alters lymphocyte sub-populations and antibody production in dwarf rats in vivo

Female dwarf rats at different ages were treated with recombinant porcine GH or with a potent sheep anti-rat GH serum. Body weight and spleen weight increased with GH and decreased with anti-GH treatment (p<0.001). Neither GH nor anti-GH treatment resulted in a change in circulating WBCs, but GH decreased, while anti-GH increased, RBC counts (p<0.001). Similarly, GH treatment tended to decrease the ratio of CD4⁺:CD8⁺ T-cells while anti-GH increased (p<0.05) the ratio. Anti-GH treatment also enhanced the animals' ability to produce specific IgG in response to KLH injection. These results indicate that GH may have a physiological role in suppressing humoral immune function but may enhance cell-mediated immunity.     

Modification of membrane cholesterol content affects electrical properties and prolactin release of cultured pituitary cells

Summary Treatment of cloned pituitary cells (GH3/B6) with cholesterol-enriched liposomes, which presumably increases membrane cholesterol content, affects the passive and active electrophysiological properties and stimulates the release of prolactin (PRL).Supported by grants from CNRS (ERA 493, ATP Endocrinologie). We thank NIAMDD for providing the reagents for PRL assay.     

Modifications of membrane cholesterol content affects electrical properties and prolactin release of cultured pituitary cells

Treatment of cloned pituitary cells (GH3/B6) with cholesterol-enriched liposomes, which presumably increases membrane cholesterol content, affects the passive and active electrophysiological properties and stimulates the release of prolactin (PRL).     

Plurihormonality in the secretory granules of the normal human pituitary. An immunoelectron microscopic study

Normal human autopsy anterior pituitary tissue from 5 cases was embedded in LR White resin and immunolabelled using silver-enhanced 5-nm protein A gold probes. Follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH), growth hormone (GH) and prolactin (PRL) were immunolocalised to the level of secretory granule. A two-sided double-labelling method was used to cross-react two hormones at a time with respect to their corresponding antibodies. All possible combinations of the six pituitary hormones were tested. Plurihormonal granules were found that contained LH + FSH, LH + TSH, and FSH + TSH. Each hormone was also found in monohormonal granules. Granule diameter was significantly larger in the pluri as opposed to monohormonal granules.     

Plurihormonality in the secretory granules of the normal human pituitary. An immunoelectron microscopic study

Summary Normal human autopsy anterior pituitary tissue from 5 cases was embedded in LR White resin and immunolabelled using silver-enhanced 5-nm protein A gold probes. Follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotrophic hormone (ACTH), growth hormone (GH) and prolactin (PRL) were immunolocalised to the level of secretory granule.A two-sided double-labelling method was used to cross-react two hormones at a time with respect to their corresponding antibodies. All possible combinations of the six pituitary hormones were tested. Plurihormonal granules were found that contained LH+FSH, LH+TSH, and FSH+TSH. Each hormone was also found in monohormonal granules. Granule diameter was significantly larger in the pluri as opposed to monohormonal granules.     

T-cell signal transduction and the role of protein kinase C

The T lymphocyte has a vital part to play in maintaining the host response to bacterial and viral infection and also appears to play a key pathological role in autoimmune diseases such as rheumatoid arthritis. In this review, we summarize the signalling pathways which trigger antigen-driven T-cell proliferation and examine the evidence which suggests that protein kinase C (PKC) is fundamental to this process. Finally, we discuss the therapeutic potential that PKC inhibitors may have in the treatment of autoimmune disease. Received 31 March 1998; received after revision 19 May 1998; accepted 19 May 1998     

Evidence for suppression of immune function by insulin-like growth factor-1 in dwarf rats in vivo

These studies were undertaken to investigate the effects of increasing or decreasing IGF-1 levels on aspects of immune function in rats. Female dwarf rats were treated with recombinant human IGF-1 or with a potent sheep anti-IGF-serum. Body weight, thymus weight and spleen weight increased with IGF-1 treatment (p<0.001), while there was no effect of anti-IGF-1 treatment when compared with the appropriate normal sheep serum (NSS) treated controls. IGF-1 treatment significantly decreased WBC and RBC counts, but increased the ratio of CD4⁺:CD8⁺ T-cells. Anti-IGF-1 serum had no effect on these parameters compared with NSS. However anti-IGF-1 was associated with increased T-cell numbers, decreased natural killer cells, and enhancement of the animals' ability to produce specific IgG in response to injection of keyhole limpet haemocyanin (KLH). These results indicate that IGF-1 may suppress immune function although increasing the size of immune organs such as spleen.These studies were part of an M.Sc. at the University of Waikato, Hamilton, New Zealand.     

Activation of cytotoxic T cells by solid tumours?

Tumour-specific cytotoxic T cells (CTLs) are among the best-defined biological anticancer weapons. Nevertheless, they often fail to control tumour growth in vivo. Many reasons for this have been evoked tumours may actively inhibit CTLs, or may protect them selves from CTL recognition by various means. However, one does not necessarily need to postulate such active immune evasion mechanisms specifically acquired by tumour cells. In this review we argue that the failure of immune protection is due to the intrinsic inability of tumours to activate an effective immune response, and that many tumours are similar to normal issues in this respect. It is striking to see that the majority of the so-called immune escape mechanisms are not specifically acquired by selected tumour cells, but are common mechanisms shared between solid tumours and normal, healthy tissues. Immune responses are poor because tumour antigens do not efficiently localize to lymph follicles in lymphoid tissues, and are not efficiently presented to CTLs in an immunogenic context. The fact that tumours do not induce CTLs but are often susceptible to lymphocyte-mediated cytotoxicity indicates that more intensified immunization protocols should result in improved clinical outcome.     

Regulation of G1 phase progression by growth factors and the extracellular matrix

Cell cycle progression is regulated by both intracellular and extracellular control mechanisms. Intracellular controls ensure that cell cycle progression is stopped in response to irregularities such as DNA damage or faulty spindle assembly, whereas extracellular factors may determine cell fate such as differentiation, proliferation or programmed cell death (apoptosis). When extracellular factors bind to receptors at the outside of the cell, signal transduction cascades are activated inside the cell that eventually lead to cellular responses. We have shown previously that MAP kinase (MAPK), one of the proteins involved in several signal transduction processes, is phosphorylated early after mitosis and translocates to the nucleus around the restriction point. The activation of MAPK is independent of cell attachment, but does require the presence of growth factors. Moreover, it appears that in Chinese hamster ovary cells, a transformed cell line, growth factors must be present early in the G1 phase for a nuclear translocation of MAPK and subsequent DNA replication to occur. When growth factors are withdrawn from the medium immediately after mitosis, MAPK is not phosphorylated, cell cycle progression is stopped and cells appear to enter a quiescent state, which may lead to apoptosis. Furthermore, in addition to this growth-factor-regulated decision point in early G1 phase, another growth-factor-sensitive period can be distinguished at the end of the G1 phase. This period is suggested to correlate with the classical restriction point (R) and may be related to cell differentiation.