In the past few years, we have demonstrated that GHRH can be produced by cells of the immune system and stimulate lymphocyte GH production and influence immune function. It is our hypothesis that lymphocyte-derived GHRH may play an autocrine or intracrine function in the regulation of lymphocyte GH synthesis which in turn may regulate the production of lymphocyte-derived IGF-1 molecules. Thus it appears that the role of GHRH in the immune system may be as important as its function in the neuroendocrine system. This proposal is concerned with the regulation of GH gene expression by GHRH and identifying the mechanism of lymphocyte-derived GHRH and GH induction of lymphocyte proliferation. Our preliminary data have identified positive (-299/-193) and negative (-193/-107) regulatory sites in the GH promoter involved in lymphocyte GH expression. The negative regulatory effect appears to be mediated by Spl/3 transcription factors. By DNase protection and gel shift analysis we plan to identify the transcription factor(s) binding to the -299/-193 region of the GH promoter that promote GH gene expression. We will investigate whether GHRH induces GH by relieving the inhibition mediated by the Spl/3 transcription factors in the -193/-107 region of the GH promoter and/or GHRH induces GH by acting to promote transcription via the positive response element in the -299/-193 region of the GH promoter. In addition to studying the mechanism of GHRH induction of GH, we will study the mechanism of GHRH and GH-induced lymphocyte proliferation. Specifically, we will determine if the proliferative effect is cell-cycle specific and involves synthesis of specific cyclin proteins. Further, we will identify signaling pathways utilized by endogenous GHRH and GH and whether they interact with GH receptor-mediated events in cells of the immune system. This will be accomplished in cells overexpressing GHRH and GH, compared to GH treatment, and the effect on activation of STAT proteins, MAP kinase activation and protein kinase C activation. Finally, we will investigate the possibility that the synthesis of lymphocyte GH in vivo occurs after treatment of animals with GHRH. It is anticipated that the results from our experiments will identify novel regulatory mechanisms that cells of the immune system utilize to produce these neuroendocrine peptides and establish the importance of lymphocyte GHRH as a cytokine-like factor involved both in the synthesis of lymphocyte GH and in cellular proliferation. It is further anticipated that the new understanding gained from the results will identify important sites for drug intervention against various immunodeficiencies including AIDS, autoimmunity, and aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041651-05
Application #
6341676
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Johnson, David R
Project Start
1997-01-01
Project End
2003-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
5
Fiscal Year
2001
Total Cost
$177,105
Indirect Cost
Name
University of Alabama Birmingham
Department
Physiology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Weigent, Douglas A (2013) Expression of lymphocyte-derived growth hormone (GH) and GH-releasing hormone receptors in aging rats. Cell Immunol 282:71-8
Weigent, Douglas A (2013) Hypoxia and cytoplasmic alkalinization upregulate growth hormone expression in lymphocytes. Cell Immunol 282:9-16
Weigent, Douglas A (2011) High molecular weight isoforms of growth hormone in cells of the immune system. Cell Immunol 271:44-52
Weigent, Douglas A (2009) Regulation of Id2 expression in EL4 T lymphoma cells overexpressing growth hormone. Cell Immunol 255:46-54
Kelley, Keith W; Weigent, Douglas A; Kooijman, Ron (2007) Protein hormones and immunity. Brain Behav Immun 21:384-92
Farmer, John T; Weigent, Douglas A (2007) Expression of insulin-like growth factor-2 receptors on EL4 lymphoma cells overexpressing growth hormone. Brain Behav Immun 21:79-85
Weigent, Douglas A; Arnold, Robyn E (2005) Expression of insulin-like growth factor-1 and insulin-like growth factor-1 receptors in EL4 lymphoma cells overexpressing growth hormone. Cell Immunol 234:54-66
Arnold, Robyn E; Weigent, Douglas A (2004) The inhibition of apoptosis in EL4 lymphoma cells overexpressing growth hormone. Neuroimmunomodulation 11:149-59
Weigent, D A; Blalock, J E (1997) Production of peptide hormones and neurotransmitters by the immune system. Chem Immunol 69:1-30