The purpose of this project is to increase our understanding of the interactions between the endocrine and immune systems in both 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 Thelper1 to Thelper2-directed immunity. On the other hand, several immune system products, such as the cytokines Tumor Necrosis Factor-a (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 furher elevated by visceral adiposity. We recently demonstrated 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 receptors called antalarmin. This antagonist has marked systemic anti-inflammatory actions. CRH was found in the ovary and endometrium where it may participate in the inflammatory phenomena of ovulation, luteolysis, blastocyst implantation, and menstruation. Antalarmin blocked implantation in rats and labor in sheep, suggesting that CRH antagonists may have clinical applications in reproductive medicine.

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U.S. National Inst/Child Hlth/Human Dev
United States
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Kino, Tomoshige; Segars, James H; Chrousos, George P (2010) The Guanine Nucleotide Exchange Factor Brx: A Link between Osmotic Stress, Inflammation and Organ Physiology and Pathophysiology. Expert Rev Endocrinol Metab 5:603-614
Nader, Nancy; Chrousos, George P; Kino, Tomoshige (2009) Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications. FASEB J 23:1572-83
Shrivastav, Shashi; Kino, Tomoshige; Cunningham, Tshaka et al. (2008) Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differentiation: implications for HIV-associated lipodystrophy. Mol Endocrinol 22:234-47
Chrousos, George P; Kino, Tomoshige (2007) Glucocorticoid action networks and complex psychiatric and/or somatic disorders. Stress 10:213-9
Kino, Tomoshige; Boos, Terrence L; Sulima, Agnieszka et al. (2007) 3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit: potential clinical implications. J Allergy Clin Immunol 120:437-44
Kino, Tomoshige; Chrousos, George P (2007) Virus-mediated modulation of the host endocrine signaling systems: clinical implications. Trends Endocrinol Metab 18:159-66
Kino, T; Rice, K C; Chrousos, G P (2007) The PPARdelta agonist GW501516 suppresses interleukin-6-mediated hepatocyte acute phase reaction via STAT3 inhibition. Eur J Clin Invest 37:425-33
Kalantaridou, S N; Zoumakis, E; Makrigiannakis, A et al. (2007) The role of corticotropin-releasing hormone in blastocyst implantation and early fetal immunotolerance. Horm Metab Res 39:474-7
Chrousos, George P (2007) Organization and Integration of the Endocrine System. Sleep Med Clin 2:125-145
Balasubramanyam, Ashok; Mersmann, Harry; Jahoor, Farook et al. (2007) Effects of transgenic expression of HIV-1 Vpr on lipid and energy metabolism in mice. Am J Physiol Endocrinol Metab 292:E40-8

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