The effect of LHRH and TRH on human interferon-γ production in vivo and in vitro

doi:10.1016/S0024-3205(98)00172-6

Life Sciences

Volume 62, Issue 22, 24 April 1998, Pages 2005-2014

https://doi.org/10.1016/S0024-3205(98)00172-6 Get rights and content

Abstract

Accumulating evidence suggests that hypothalamic luteinizing hormone-releasing hormone (LHRH) and thyrotropin-releasing hormone (TRH) are two hypophysiotropic factors which modulate the immune response. The aim of the present study was to determine the in vivo effects of an intravenous bolus of LHRH and TRH on plasma interferon (IFN)-γ production in five normoprolactinemic women with irregular menstrual cycles. We also determined prolactin (PRL), thyrotropin (TSH), follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels before and after intravenous administration of LHRH and TRH. The results demonstrate that intravenous bolus of LHRH/TRH increases plasma IFN-γ levels, with the maximum response 45 min after in vivo administration of hypothalamic peptides and after peak levels of adenohypophyseal hormones (PRL: 15 min; TSH: 30 min; FSH: 30 min; LH: 30 min). In order to investigate a possible direct action of hypothalamic hormones on immune cells, we also evaluated, in the same subjects, the influence of LHRH and TRH on IFN-γ production by human peripheral blood mononuclear cells (PBMCs), collected before the intravenous administration of the peptides and stimulated in vitro with bacterial superantigen staphylococcal enterotoxin A (SEA) and concanavalin A (Con A). LHRH and TRH, separately and together, significantly enhanced in vitro IFN-γ production by SEA- and ConA-activated PBMCs. The present results suggest that hypothalamic peptides (LHRH and TRH) directly, and/or indirectly pituitary hormones (PRL, TSH, FSH, and LH) or IL-2, have stimulatory effect on IFN-γ producing cells and are further evidence of interactions between the neuroendocrine and immune systems.

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GnRH-I treatment increases the proliferation of Epstein-Barr virus (EBV)-transformed B lymphocytes and human peripheral blood mononuclear cells (PBMCs). GnRH-I treatment in stimulated PBMCs increases the expression of interleukin-2Rγ (IL-2Rγ) mRNA and synthesis of interferon γ (IFN-γ) (Chen et al., 1999; Grasso et al., 1998; Tanriverdi et al., 2005; Tanriverdi et al., 2004). The immunostimulatory effect of GnRH-I has also been suggested by the results of in vivo studies, in which GnRH-I antagonist administration in mouse models of autoimmune diseases reduced Ig levels (Jacobson et al., 1994).
Immune system function changes during aging, but the molecular mechanisms of this phenomenon are not fully understood. The present study identified pathways that are associated with age-associated changes in human B lymphocytes. Initial in silico analysis of 1355 genes involved in aging revealed the strongest association (p = 4.36E-21) with the gonadotropin-releasing hormone receptor (GnRHR) pathway. Extended analysis of 2736 aging-related genes using updated databases confirmed such association (p = 2.41E-16). Genes involved in both aging and the GnRHR pathway were significantly involved in lymphocyte B and T activation and aging-related phenotypes, including hyperinsulinemia and diabetes, arthritis, cerebrovascular disease, and cancers. We, therefore, examined non-tumorigenic Epstein-Barr virus (EBV)-transformed B-lymphocyte cell lines that originated from 12 young subjects (20–31 years old) and 10 centenarians (100–102 years old). Gonadotropin-releasing hormone I (GnRH-I) and GnRHR levels did not depend on the age of the cell donors. Inhibition of the GnRHR pathway age-independently decreased cell proliferation (p < 0.001) and increased apoptosis (p < 0.001). However, the decrease in immunoglobulin G synthesis (p < 0.01) was twice as high in centenarian cells than in young cells.
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Quantifying Observational Evidence for Risk of Fatal and Nonfatal Cardiovascular Disease Following Androgen Deprivation Therapy for Prostate Cancer: A Meta-analysis
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Experimental studies have shown that GnRH agonists can activate T lymphocytes and induce their proliferation. However, these effects were not observed when using GnRH antagonists [56,58]. These mechanisms could potentially explain the strong association we found between GnRH agonists and nonfatal or fatal MI and stroke.
Whether androgen deprivation therapy (ADT) for men with prostate cancer (PCa) increases the risk of cardiovascular disease (CVD) remains controversial. Pooled analyses using data from randomised controlled trials suggest no increased risk of fatal CVD following ADT, but no pooled analyses exist for observational studies.
To perform a meta-analysis using observational data on ADT and risk of CVD events in men with PCa.
PubMed and Embase were searched using predefined inclusion criteria to perform meta-analyses on associations between types of ADT and nonfatal and fatal CVD outcomes using information from observational studies. Random effects meta-analyses were conducted to estimate relative risks (RRs) and 95% confidence intervals (CIs).
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Observational data show a consistent positive association between ADT and the risk of CVD. This finding supports the need for future randomised trials of PCa patients that include older patients and men with multiple comorbidities to better reflect the general population.
We investigated all the available data from observational studies on hormonal treatment for prostate cancer and its possible cardiovascular adverse effects. We found consistent evidence that this treatment may increase the risk of cardiovascular disease.
The thyrotropin-releasing hormone (TRH)-immune system homeostatic hypothesis
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Decades of research have established that the biological functions of thyrotropin-releasing hormone (TRH) extend far beyond its role as a regulator of the hypothalamic-pituitary–thyroid axis. Gary et al. [Gary, K.A., Sevarino, K.A., Yarbrough, G.G., Prange, A.J. Jr., Winokur, A. (2003). The thyrotropin-releasing hormone (TRH) hypothesis of homeostatic regulation: implications for TRH-based therapeutics. J Pharmacol Exp Ther 305(2):410–416.] and Yarbrough et al. [Yarbrough, G.G., Kamath, J., Winokur, A., Prange, A.J. Jr. (2007). Thyrotropin-releasing hormone (TRH) in the neuroaxis: therapeutic effects reflect physiological functions and molecular actions. Med Hypotheses 69(6):1249–1256.] provided a functional framework, predicated on its global homeostatic influences, to conceptualize the numerous interactions of TRH with the central nervous system (CNS) and endocrine system. Herein, we profer a similar analysis to interactions of TRH with the immune system.
Autocrine/paracrine cellular signaling motifs of TRH and TRH receptors are expressed in several tissues and organs of the immune system. Consistent with this functional distribution, in vitro and in vivo evidence suggests a critical role for TRH during the developmental stages of the immune system as well as its numerous interactions with the fully developed immune system. Considerable evidence supports a pivotal role for TRH in the pathophysiology of the inflammatory process with specific relevance to the “cytokine-induced sickness behavior” paradigm. These findings, combined with a number of documented clinical actions of TRH strongly support a potential utility of TRH-based therapeutics in select inflammatory disorders.
Similar to its global role in behavioral and energy homeostasis a homeostatic role for TRH in its interactions with the immune system is consonant with the large body of available data. Recent advances in the field of immunology provide a significant opportunity for investigation of the TRH-immune system homeostatic hypothesis. Moreover, this hypothesis may provide a foundation for the development of TRH-based therapeutics for certain medical and psychiatric disorders involving immune dysfunction.
Neuroendocrine regulation of natural immunity
2005, NeuroImmune Biology
Citation Excerpt :
TSHR are not detectable on foetal and neonatal immune cells. TSH significantly stimulated IL-2 and IL-12, IL-1β responses and enhanced the phagocytic activity of DCs from adult animals, enhanced the proliferative response of murine spleen cells to IL-2, significantly increased IL-2 induced NK cell cytotoxicity and enhanced the expression of MHC-II by human thyroid epithelial cells [149,152-156]. In bone marrow cells IL-6, IFNβ, TNFα, TNFβ, TGFβ2, and lymphotoxin-β responses were reproducibly induced by TSH [158].
Natural killer (NK) cells, γδ T lymphocytes and CD5 + B lymphocytes are key effector cells in the natural immune system. These cells utilize germ-line coded receptors that recognize highly conserved, homologous epitopes (homotopes). Cytokines, hormones and neurotransmitters regulate natural immunity. Under physiological conditions the natural immune system is regulated similarly to the adaptive immune system: growth and lactogenic hormones (GLH), insulin-like growth factor-I (IGF-I), insulin, leptin, some steroid (glucocorticoid at physiological concentrations, dehydroepiandrosterone and some of its derivatives) and thyroid hormones are stimulatory. The peptides of the hypothalamus-pituitary-adrenal axis (CRF, AVR ACTH, αMSH, βEND) exert an immunosuppressive, anti-inflammatory and anti-pyretic effect. Opioid peptides and estradiol are immunomodulators that promote some immune activities while inhibiting others. High (pathophysiological) levels of glucocorticoids, progesterone and testosterone act as immunosuppressive hormones. Beta-adrenergic agents are immunosuppressive and antiinflammatory, whereas cholinergic agents promote immunity and inflammation. Substance P and calcitonin-gene related peptide are pro-inflammatory and promote immunity, whereas somatostatin is an antagonoist of these neuropeptides.
Mild infection or a sublethal dose of endotoxin elicits a brief elevation of GH and PRL in the serum. Severe trauma, sepsis and shock results in the elevation of TNFα, IL-1 and IL-6 in the blood stream, the GLH-IGF-I axis is suppressed, whereas the hypothalamus-pituitary-adrenal axis is activated. LH, FSH, estrogens, androgens, progesterone, and thyroid hormones all decline during infection and endotoxin shock, as a rule. Leptin, insulin, glucagon, α-MSH, endorphin, and arginine vasopressin are increased during endotoxemia. A “sympathetic outflow” leads to elevated blood levels of catecholamines. Fever and catabolism prevails, whereas acute phase proteins in the liver, cell proliferation in the bone marrow, and protein synthesis by leukocytes are increased. This is an acute emergency reaction to save the organism after the adaptive immune system has failed to contain and eliminate the pathogenic agent. During sepsis and endotoxin shock, glucocorticoids potentiate the production of acute phase proteins and regulate pro-inflammatory cytokine production. Catecholamines also inhibit inflammatory responses and promote, even initiate, the acute phase response. Leptin regulates energy metabolism and it is a major stimulator of the immune system. If the acute phase reaction fails to protect the host, shock will develop and death will follow.
The acute phase response leads to immunoconversion, which involves the suppression of the T-cell regulated adaptive immune system and the amplification of natural immunity. Natural antibodies, C-reactive -, endotoxin binding- and mannose binding proteins are boosted and serve as polyspecific recognition molecules for leukocytes. The natural immune system provides the first and the last line of host defence and its functional integrity and massive activation is largely dependent on the neuroendocrine system.
Effect of growth hormone-releasing hormone (GHRH) and GHRH antagonist (MZ-4-71) on interferon-γ secretion from human peripheral blood mononuclear cells in vitro
2004, Neuropeptides
Numerous reports indicate close interactions between the neuroendocrine and the immune systems. Hypothalamic neuropeptide, growth hormone-releasing hormone (GHRH) stimulates growth hormone (GH) secretion from the anterior pituitary gland, but recently some immunomodulatory properties of this peptide have also been demonstrated. In the present studies we evaluated the effect of human synthetic GHRH(1–44)NH₂ and GHRH antagonist (MZ-4-71) on interferon (IFN)-γ secretion from human peripheral blood mononuclear cells (PBMC). GHRH(1–44)NH₂ at 10⁻¹⁰, 10⁻⁸ and 10⁻⁶ M concentrations significantly (p<0.05) increased the IFN-γ level in supernatants of cultured cells, as compared with the controls. GHRH antagonist (MZ-4-71) at 10⁻¹⁰, 10⁻⁸ and 10⁻⁶ M concentrations diminished the IFN-γ level in supernatants in a dose-dependent manner, but statistically significant differences were observed only at 10⁻⁸ M and 10⁻⁶ M (p<0.05 vs controls). Our results demonstrate that GHRH and GHRH antagonist MZ-4-71 can modulate IFN-γ secretion in vitro by human peripheral blood mononuclear cells.
Steroid hormones
2003, NeuroImmune Biology
The steroid hormones that play major roles in the neuroimmune regulatory network include glucocorticoids, aldosterone, estrogens, androgens and vitamin D. These hormones have cytoplasmic or nuclear receptors, which are transcription factors that directly regulate gene expression. Glucocorticoids are produced in the adrenal gland as well as the thymus and are fundamental to immune function. Physiological levels are required for the normal development and functioning of the immune system. Under pathophysiological conditions the serum level of glucocorticoids is elevated, which plays an important role in the suppression of the adoptive immune response that depends on T lymphocytes. Glucocorticoids also exert a powerful anti-inflammatory effect. Elevated glucocorticoids during acute phase reactions augment the production of natural antibodies and support the production of acute phase proteins by the liver.
Luteinizing hormone releasing hormone and gonadotropins exert a direct regulatory influenceon the immune system, in addition to the regulation of sex steroid hormones. In turn immunederived cytokines regulate the production of gonadotropins. These mechanisms insure the coordination of reproduction with health status and prevent inopportune conception.
Estrogens regulate the thymus and suppress cell-mediated immune reactions. The antibodyresponse and natural immunity (NK cytotoxicity, phagocytosis) are augmented by estradiol. Testosterone is immunosuppressive during trauma and shock. Many of the immunological effects of testosterone are due to its conversion to estradiol by aromatase in the thymus and in other lymphoid organs. The adrenal androgen, dehydroepyandrosterone stimulates immune reactions in experimental animals and in man. It antagonizes the immunosuppressive effect of glucocorticoids and its age-related decline may contribute to the immunodeficiency that develops in elderly individuals. Progesterone is a powerful immunosupressive hormone. It plays a major role in the protection of the fetus during mammalian reproduction. Progesterone also contributes to the generation of self tolerance and protects against the excessive activation of the immune system.
1,25-dihydroxy vitamin D3 (VD3) is a major immunoregulator with a powerful immunosuppressive potential. Deficiency of VD3 plays an important role in the development of autoimmune disease. VD3 is also required for normal immune function and for proper defense against infectious disease and cancer.

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The effect of LHRH and TRH on human interferon-γ production in vivo and in vitro

Abstract

Neuropeptides

Am. J. Med. Sci.

Neuropeptides

Immunobiology

Clin. Immunol. Immunopathol.

Life Sci.

Trends Endocrinol. Metab.

Clin. Immunol. Immunopathol.

Human Immunol.

Peptides

Regul. Pept.

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Prog. Neuroendocrinimmunol.

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Endocrinology

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Endocrinology

Prog. Neuroendocrinimmunol.

Endocrinology

Endocrinology

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Immunol. Cell Biol.

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Scand. J. Clin. Lab. Invest.

Endocrinology

Progr. Neuroendocrinoimmunol.