The neuroendocrine and immune systems communicate bi-directionally. There are no accepted markers to measure their interactions, or disorders. Neuropeptide hormones and cytokines regulate cells of both systems, but little is known of the intracellular steps between binding to the surface receptors and cellular responses when cytokines and neuropeptides cross systems. The goal of this project is to begin to understand how these multiple signals are integrated at the intracellular level and subsequently alter immune and/or neuroendocrine cell function. Preliminary data suggest that the signal pathways converge and mutually affect the activity of the transcription factor, Nf-kappaB. The project is divided into three aims to investigate whether Nf-kappaB has a pivotal role in the integration of immune and neuroendocrine system signals. 1) Gel shift studies will determine the extent and specificity of neuropeptide hormones and cytokines to affect Nf-kappB in lymphoid and neuroendocrine cells. 2) A luciferase cis-reporter gene system will be used to measure changes in Nf-kappaB activity due to individual and multiple neuropeptide and cytokine signal molecules. Also, specific inhibitors of the Nf-kappaB pathway will be used to determine in a quantitative manner the effect modulating this transcription factor has on in vitro antibody and cytokine production. 3) Finally, studies using a Nf-kappaB1 gene knockout mouse model will be used for studies of the relative importance of this Nf-kappaB component for neuropeptide and cytokine effects on lymphoid and pituitary functioning. These studies will show the impact and specificity of the Nf-kappaB pathway in mediating selected neuropeptide and cytokine regulation of immune and neuroendocrine interactions. Inhibitors of Nf-kappaB are being developed, primarily as anti-inflammatory agents. Understanding the role of Nf-kappaB in neuroendocrine-immune interactions may suggest novel markers and therapeutic targets. In turn, these might have great impact for treatment of diseases involving the nervous and immune systems, such as myasthenia gravis or multiple sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039974-03
Application #
6540248
Study Section
Special Emphasis Panel (ZRG1-IFCN-1 (03))
Program Officer
Nunn, Michael
Project Start
2000-04-01
Project End
2003-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$260,750
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Smith, Eric M (2008) Neuropeptides as signal molecules in common with leukocytes and the hypothalamic-pituitary-adrenal axis. Brain Behav Immun 22:3-14
Smith, Eric M; Gregg, Mike; Hashemi, Farhad et al. (2006) Corticotropin Releasing Factor (CRF) activation of NF-kappaB-directed transcription in leukocytes. Cell Mol Neurobiol 26:1021-36
Tu, Huolin; Rady, Peter L; Juelich, Terry et al. (2005) Cytokine regulation of tryptophan metabolism in the hypothalamic-pituitary-adrenal (HPA) axis: implications for protective and toxic consequences in neuroendocrine regulation. Cell Mol Neurobiol 25:673-80
Johnson, Eve W; Hughes Jr, Thomas K; Smith, Eric M (2005) ACTH enhancement of T-lymphocyte cytotoxic responses. Cell Mol Neurobiol 25:743-57
Rady, Peter L; Matalon, Reuben; Grady, James et al. (2004) Comprehensive analysis of genetic polymorphisms in the interleukin-10 promoter: implications for immune regulation in specific ethnic populations. Genet Test 8:194-203
Smith, Eric M; Dalmeida, William; Hughes, Thomas K (2004) Signaling pathway-related gene expression in neuroimmunoregulation. J Neuroimmunol 147:138-40
Smith, Eric M (2003) Opioid peptides in immune cells. Adv Exp Med Biol 521:51-68
Tu, Huolin; Juelich, Terry; Smith, Eric M et al. (2003) Evidence for endogenous interleukin-10 during nociception. J Neuroimmunol 139:145-9
Hogan, Dale; Morrow, Jonathan D; Smith, Eric M et al. (2003) Interleukin-6 alters sleep of rats. J Neuroimmunol 137:59-66
Johnson, E W; Hughes Jr, T K; Smith, E M (2001) ACTH receptor distribution and modulation among murine mononuclear leukocyte populations. J Biol Regul Homeost Agents 15:156-62