PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)

Prolactin (PRL) and Its Receptor: Actions, Signal Transduction Pathways and Phenotypes Observed in PRL Receptor Knockout Mice

Adequate intakes of vitamins and trace elements are required for the immune system to function efficiently. Micronutrient deficiency suppresses immune functions by affecting the innate T-cell-mediated

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Contribution of Selected Vitamins and Trace Elements to Immune Function

Background
Vaccines have been the main global weapon to minimise the impact of influenza in the elderly for the last four decades and are recommended worldwide for individuals aged 65 years or older The primary goal of influenza vaccination in the elderly is to reduce the risk of complications among persons who are most vulnerable

Objectives
To assess the effectiveness of vaccines in preventing influenza, influenza-like illness (ILI), hospital admissions, complications and mortality in the elderly 
To identify and appraise comparative studies evaluating the effects of influenza vaccines in the elderly 
To document types and frequency of adverse effects associated with influenza vaccines in the elderly

Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register (The Cochrane Library 2009, issue 4); MEDLINE (January 1966 to October Week 1 2009); EMBASE (1974 to October 2009) and Web of Science (1974 to October 2009)

Selection criteria
Randomised controlled trials (RCTs), quasi-RCTs, cohort and case-control studies assessing efficacy against influenza (laboratory-confirmed cases) or effectiveness against influenza-like illness (ILI) or safety Any influenza vaccine given independently, in any dose, preparation or time schedule, compared with placebo or with no intervention was considered

Data collection and analysis
We grouped reports first according to the setting of the study (community or long-term care facilities) and then by level of viral circulation and vaccine matching We further stratified by co-administration of pneumococcal polysaccharide vaccine (PPV) and by different types of influenza vaccines We analysed the following outcomes: influenza, influenza-like illness, hospital admissions, complications and deaths

Main results
We included 75 studies Overall we identified 100 data sets We identified one RCT assessing efficacy and effectiveness Although this seemed to show an effect against influenza symptoms it was underpowered to detect any effect on complications (1348 participants) The remainder of our evidence base included non-RCTs Due to the general low quality of non-RCTs and the likely presence of biases, which make interpretation of these data difficult and any firm conclusions potentially misleading, we were unable to reach clear conclusions about the effects of the vaccines in the elderly

Authors' conclusions
The available evidence is of poor quality and provides no guidance regarding the safety, efficacy or effectiveness of influenza vaccines for people aged 65 years or older To resolve the uncertainty, an adequately powered publicly-funded randomised, placebo-controlled trial run over several seasons should be undertaken

Vaccines for preventing influenza in the elderly

Zinc is known to be essential for all highly proliferating cells in the human body, especially the immune system. A variety of in vivo and in vitro effects of zinc on immune cells mainly depend on the zinc concentration. All kinds of immune cells show decreased function after zinc depletion. In monocytes, all functions are impaired, whereas in natural killer cells, cytotoxicity is decreased, and in neutrophil granulocytes, phagocytosis is reduced. The normal functions of T cells are impaired, but autoreactivity and alloreactivity are increased. B cells undergo apoptosis. Impaired immune functions due to zinc deficiency are shown to be reversed by an adequate zinc supplementation, which must be adapted to the actual requirements of the patient. High dosages of zinc evoke negative effects on immune cells and show alterations that are similar to those observed with zinc deficiency. Furthermore, when peripheral blood mononuclear cells are incubated with zinc in vitro, the release of cytokines such as interleukins (IL)-1 and -6, tumor necrosis factor-alpha, soluble IL-2R and interferon-gamma is induced. In a concentration of 100 micro mol/L, zinc suppresses natural killer cell killing and T-cell functions whereas monocytes are activated directly, and in a concentration of 500 micro mol/L, zinc evokes a direct chemotactic activation of neutrophil granulocytes. All of these effects are discussed in this short overview.

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Zinc-Altered Immune Function

Zn is an essential trace element for all organisms. In human subjects body growth and development is strictly dependent on Zn. The nervous, reproductive and immune systems are particularly influenced by Zn deficiency, as well as by increased levels of Zn. The relationship between Zn and the immune system is complex, since there are four different types of influence associated with Zn. (1) The dietary intake and the resorption of Zn depends on the composition of the diet and also on age and disease status. (2) Zn is a cofactor in more than 300 enzymes influencing various organ functions having a secondary effect on the immune system. (3) Direct effects of Zn on the production, maturation and function of leucocytes. (4) Zn influences the function of immunostimulants used in the experimental systems. Here we summarize all four types of influence on the immune function. Nutritional aspects of Zn, the physiology of Zn, the influence of Zn on enzymes and cellular functions, direct effects of Zn on leucocytes at the cellular and molecular level, Zn-altered function of immunostimulants and the therapeutic use of Zn will be discussed in detail.

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Zinc and the immune system

Objective to evaluate whether oral supplementation with zinc or zinc/arginine increases the antibody response to influenza vaccine or modulates the lymphocyte phenotype in elderly subjects. Design a randomized controlled trial with two supplemented groups and one control group. Setting a community nursing home. Participants 384 subjects aged 64-100 (mean age 82 years) examined in three separate studies. Intervention oral supplementation with zinc (400 mg/day) or zinc plus arginine (4 g/day) for 60 days starting 15 days before influenza vaccination. The control groups received vaccine only. Measurements haematological and nutritional indices, antibody titre against influenza viral antigens, lymphocyte phenotype. Results supplementation with zinc or zinc plus arginine increased zinc plasma concentrations restoring the age-related impairment in zinc concentrations to values found in younger people. The antibody titre against influenza viral antigens was not increased in zinc or zinc/arginine supplemented groups in comparison with subjects receiving vaccine alone. The number of CD3, CD4 or CD8 lymphocytes was not affected by zinc or zinc/arginine supplementation. Conclusion prolonged supplementation with zinc or zinc/arginine restores zinc plasma concentrations but is ineffective in inducing or ameliorating the antibody response after influenza vaccination in elderly subjects.

Effect of zinc or zinc plus arginine supplementation on antibody titre and lymphocyte subsets after influenza vaccination in elderly subjects: a randomized controlled trial

The microtubule-associated protein MAP2 is a cytoskeletal protein that plays a regulatory role in neuronal plasticity and in maintaining the morphology of differentiated neurons. MAP2 distribution was assessed in hippocampus and cerebellum of young and old rats by quantitative immunohistochemistry. In old vs young rats, densitometric analysis showed a significant decrease of MAP2 immunoreactivity in the hippocampus CA1 field (-93%), whereas no difference was found in cerebellar MAP2 distribution. These preliminary data suggest that in areas of the brain involved in memory acquisition and consolidation, MAP2-dependent neuroplasticity and structural integrity are significantly decreased in aging.

https://journals.sagepub.com/doi/pdf/10.1177/002215540104900818

Distribution of MAP2 in Hippocampus and Cerebellum of Young and Old Rats by Quantitative Immunohistochemistry

The age-dependent changes in thyroid-hormone blood levels and the effects of in vivo and in vitro thyroid-hormone administration on both basal and lymphokine-induced spleen cell natural killer (NK) activities have been investigated in young and old Balb/c mice Both thyroxine (T4) and triiodothyronine (T3) plasma levels decline progressively with increasing age of the mice, displaying in 25-month-old mice only 50 and 60% of the T4 and T3 blood levels, respectively, found in young mice In vivo T4 administration to old mice causes a significant increment in endogenous NK activity (22-fold increase), which approaches the values observed in young animals, while it does not modify NK activity in young mice The T4 injection in old mice does not induce changes in the lymphocyte sub-populations When T4 is administered in vitro alone or in combination with interferon (IFN) and/or interleukin 2 (IL-2), no effect is observed either on basal activity or IL-2-induced cytotoxicity, whereas the IFN sensitivity of spleen cells from old mice is significantly recovered (4-fold increase) T4 is able to increase IFN-induced cytotoxicity even when administered in vitro simultaneously with IFN to the cytotoxic assay (15- and 27-fold increases in young and old mice, respectively) Under these conditions, IFN alone is not able to exert any boosting effect even at a young age In vivo propylthiouracil (PTU) administration completely abrogates the IFN responsiveness of spleen cells in young mice The interruption of the PTU treatment results in a recovery of IFN-inducible NK cytotoxicity Taken together, our findings point out the important role of thyroid hormones in the modulation of NK cell activity and provide a new insight into the mechanisms by which the endocrine system is able to influence the expression of natural immunity

Recovery of spleen cell natural killer activity by thyroid hormone treatment in old mice.

Role of prolactin in the modulation of NK and lak cell activity after short- or long-term morphine administration in neoplastic patients

The cytotoxic activity of Natural Killer (NK) and Lymphokine Activated Killer (LAK) cells in neoplastic patients with or without antalgic treatment was studied. NK cell activity was found reduced in untreated neoplastic patients when compared to healthy subjects. The atalgic treatment with morphine (orally or intrathecally administered) was able to significantly reduce the mean values of NK cell activity found in cancer patients. In three patients the cytotoxicity of NK cells significantly decreased during transfer from oral to intrathecal administration of morphine. In contrast to the NK cell function, the development of LAK cell activity significantly increased in neoplastic patients when compared to healthy controls. Further increments were obtained during treatment with morphine. The oral treatment with morphine was able to determine a higher induction of LAK cells than the intrathecal administration of the drug. Besides providing new knowledge on the effect of morphine on immune system our findings suggest that, in order to include neoplastic patients in clinical trials of adoptive immunotherapy with LAK cells and interleukin-2 (IL-2), the antalgic therapy with oral administration of morphine may represent a better solution than the intrathecal administration of the drug.

G. Di Stefano

Papers

Effect of zinc or zinc plus arginine supplementation on antibody titre and lymphocyte subsets after influenza vaccination in elderly subjects: a randomized controlled trial

Distribution of MAP2 in Hippocampus and Cerebellum of Young and Old Rats by Quantitative Immunohistochemistry

Recovery of spleen cell natural killer activity by thyroid hormone treatment in old mice.

Role of prolactin in the modulation of NK and lak cell activity after short- or long-term morphine administration in neoplastic patients

Evaluation of NK and LAK cell activities in neoplastic patients during treatment with morphine.