We have performed several lines of experiments to examine the interactions between the endocrine and immune systems particularly by focusing on viral infection, including that by the human immunodeficiency syndrome type-1 (HIV-1), cytomegalovirus (CMV) or Newcastle disease (NDV) virus. Viruses are known as 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 may further contribute to viral expansion and pathogenesis. Indeed, we demonstrated that HIV-1 accessory protein Vpr suppresses PPAR-gamma activity playing a potentially important role in the development of the characteristic AIDS-associated lipodystrophy and insulin-resistance syndrome. This viral protein can be found in sera of the AIDS patients and changes activity of the cells uninfected by the HIV-1 virus, such as hepatocytes and adipocytes, by penetrating their cell membrane. In this fiscal year, we published one manuscript that demonstrates the effect of Vpr on the PPAR-beta/delta: Vpr enhanced the transcriptional activity of this receptor, which resulted in reduced activity of the pyruvate dehydrogenase complex through upregulation of the pyruvate dehydrogenase kinase 4 expression, and in stimulation of beta-oxydation and oxygen consumption by mitochondria. These results suggest that Vpr contributes to impaired energy metabolism and increased energy expenditure frequently observed in HIV-1-infected patients. In dendritic cells (DCs), 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, including p300 and p160-type histone acetyltransferase coactivators, possibly altering secretion/production of interferons and other cytokines by these cells. Since NOR1, one member of NR4A group nuclear receptors, was the most highly regulated NR upon viral infection in DCs, we obtained NOR1 knockout mice from Dr. Conneely, the Baylor Collage of Medicine, and have examined impact of pathogen infection to the action of DCs purified from NOR1 knockout mice. DCs from these mice showed a significant defect in the response of interleukin (IL)-12 to viral infection compared to those from wild type mice, while NOR-1 stimulated the IL-12 p40 promoter activity through its DNA response elements in reporter assays. NOR-1 knockout mice demonstrated significant reduction of IL-12 production against infection of Toxoplasma gondii, a protozoa against which IL-12 acts as an essential component for host defense. We are currently examining details of molecular regulation of NOR-1 on IL-12 production both in the cellular and animal systems. In the same line of experiments, we found that CMV and NDV stimulated IL-10 expression in DCs, and glucocorticoids further potentiated such virus-induced expression of this cytokine. Since IL-10 inhibits synthesis of pro-inflammatory cytokines and has ability to suppress antigen presentation by DCs and monocytes, synergistic activation of IL-10 by glucocorticoids may explain why exposure to stress and subsequent activation of the HPA axis increases susceptibility to viral infection, and possibly, subsequent development of viral-associated disorders, such as asthma, atherosclerosis and cancers. We found that viral infection activated the extracellular signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase family, which in turn phosphorylated the human GR at serine located at amino acid position 211 and enhanced the transcriptional activity of GR on the IL-10 promoter. In this fiscal year, we published one manuscript based on these results.

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Agarwal, Neeti; Iyer, Dinakar; Patel, Sanjeet G et al. (2013) HIV-1 Vpr induces adipose dysfunction in vivo through reciprocal effects on PPAR/GR co-regulation. Sci Transl Med 5:213ra164
Ng, Sinnie Sin Man; Li, Andrew; Pavlakis, George N et al. (2013) Viral infection increases glucocorticoid-induced interleukin-10 production through ERK-mediated phosphorylation of the glucocorticoid receptor in dendritic cells: potential clinical implications. PLoS One 8:e63587
Shrivastav, Shashi; Zhang, Liyan; Okamoto, Koji et al. (2013) HIV-1 Vpr enhances PPARβ/δ-mediated transcription, increases PDK4 expression, and reduces PDC activity. Mol Endocrinol 27:1564-76
Kino, Tomoshige (2012) Circadian rhythms of glucocorticoid hormone actions in target tissues: potential clinical implications. Sci Signal 5:pt4
Kino, T; Charmandari, E; Chrousos, G P (2011) Glucocorticoid receptor: implications for rheumatic diseases. Clin Exp Rheumatol 29:S32-41
Kino, Tomoshige; Chrousos, George P (2011) Circadian CLOCK-mediated regulation of target-tissue sensitivity to glucocorticoids: implications for cardiometabolic diseases. Endocr Dev 20:116-26
Ng, Sinnie Sin Man; Chang, Tsung-Hsien; Tailor, Prafullakumar et al. (2011) Virus-induced differential expression of nuclear receptors and coregulators in dendritic cells: implication to interferon production. FEBS Lett 585:1331-7
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
Kino, Tomoshige; Chrousos, George P (2009) Tumor-associated, estrogen receptor-related antigen EBAG9: linking intracellular vesicle trafficking, immune homeostasis, and malignancy. Mol Interv 9:294-8
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

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