Endocrine-immune-reproductive System Interactions

Eunice Kennedy Shriver National Institute Of Child Health & Human Development

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Abstract

The purpose of this project is to increase our understanding of the interactions between the endocrine and immune systems at three levels, cultured cells, experimental animals and humans. The stress hormones glucocorticoids and catecholamines inhibit the secretion of Interleukin (IL)-12 and stimulate the secretion of IL-10 by monocytes macrophages, leading to a shift from Thelper-1 to Thelper-2-directed immunity. These hormones also influence development and functions of newly identified T-cell lineages, Thelper17 and Thelper-reg, the former of which was recently shown to play a major role in the pathogenesis of autoimmune disorders. On the other hand, several immune system products, such as the cytokines Tumor Necrosis Factor-alpha (TNF-alpha), IL-1, and IL-6, activate the hypothalamic-pituitary-adrenal axis and through it suppress and restrain the inflammatory immune response. Human fat examined in situ by microperfusion produces not only leptin, but also TNF-alpha and IL-6. The secretion of these cytokines has a circadian rhythm that is influenced by sleep, while their circulating levels increase proportionally to the BMI and are further elevated by visceral adiposity. IL-6 concentrations are elevated in patients with depression, idiopathic insomnia and sleep apnea. Enbrel, an anti-TNF-alpha biological, decreases IL-6 concentrations, improves sleep apnea indices and decreases sleepiness. In depression, the circadian rhythm of IL-6 is inverted with highest levels in the morning, correlating strongly with the affect of these patients. Sleep deprivation results in a fall of performance and an increase in fatigue associated with an elevation of plasma IL-6 concentrations. Napping decreases IL-6 and improves performance. We recently showed that two small molecules an IL-6 antagonist and a PPAR-delta agonist have strong anti-inflammatory activities via STAT3 inhibition. The former compound, TB-2-081, interacted with the gp130 subunit of the IL-6-type receptors and blocked the activity not only of IL-6 but also of LIF, Oncostatin M and IL-11. A major change in the cell was the inhibition of the tyrosine phosphorylation of the STAT3 transcription factor. The latter compound, GW50516, inhibited the production of several acute phase reactants by hepatic cells showing thus major anti-inflammatory activity. This effect was also mediated by inhibition of STAT3 activity at the promoter of responsive genes. We had demonstrated earlier that corticotropin-releasing hormone (CRH) is produced locally at sites of inflammation and has profound pro-inflammatory effects at an autocrine/paracrine level. CRH is a potent degranulator of mast cells, a phenomenon that can be inhibited by a nonpeptide CRH antagonist, specific for type 1 CRH receptors called antalarmin. This antagonist has marked systemic anti-inflammatory actions in an animal model of rheumatoid arthritis, and blocks Shigella -related seizures and visceral pain in animal models. CRH was found in the ovary and endometrium, where it participates in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstruation. Antalarmin blocked embryo implantation in rats and labor in sheep, suggesting that CRH antagonists may have clinical applications in reproductive medicine. Finally, viruses, including the human immunodeficiency syndrome type-1 (HIV-1), cytomegalovirus (CMV), and Newcastle disease (NDV) viruses, are potent activators and modulators of the host immune and endocrine systems, influencing hormonal actions in host tissues, such as leukocytes, adipose tissue and skeletal muscles. These effects further contribute to viral expansion and pathogenesis. Indeed, we recently demonstrated that HIV-1 accessory molecule Vpr suppresses PPAR-gamma activity playing a potentially important role in the development of the characteristic AIDS-associated lipodystrophy and insulin-resistance syndrome. In dendritic cells, which play a central role in the recognition and presentation of viral antigens, infection of CMV or NDV and perhaps HIV-1, causes dramatic changes in the expression of a group of nuclear hormone receptors, including the glucocorticoid and estrogen receptors, as well as of several transcriptional co-regulators, such as p300 and p160-type histone acetyltransferase coactivators, possibly altering secretion/production of interferons and other cytokines by these cells.