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The Influence of Aging and Sex Hormones on Expression of Growth Hormone-Releasing Hormone in the Human Immune System¹

Department of Obstetrics and Gynecology, University of Wisconsin, and Wisconsin Regional Primate Research Center, Madison, Wisconsin 53792

Address all correspondence and requests for reprints to: Omid Khorram, M.D., Ph.D., Department of Obstetrics and Gynecology, Box 489, Harbor-University of California-Los Angeles Medical Center, 1000 West Carson Street, Torrance, California 90509. E-mail: Okhorram{at}rei.edu

Abstract

GHRH is a neuropeptide that has also been localized to the immune system. The physiological function of GHRH in the immune system has not been elucidated. This study was conducted to determine whether immune GHRH expression is altered in certain pathological states, such as immune cell tumors, and whether gender, aging, and alterations in the sex steroid milieu influence the expression of this peptide in immune cells.

Using double color flow cytometry, GHRH protein was found to be expressed in less than 2% of peripheral blood mononuclear cells (PBMC). Monocytes and B and T cells all expressed GHRH protein, although a greater percentage of T cells compared with B cells and monocytes expressed GHRH (5- to 7-fold). Semiquantitative RT-PCR was used to quantify GHRH messenger ribonucleic acid (mRNA) in PBMC and several immune cell-derived tumors. PBMC and granulocytes expressed low levels of GHRH mRNA with relatively higher levels of expression in monocytes. The tumor cell lines CEMX 174 (B/T cells), HUT 78 (T cells), WIL2-N (B cells), U937 (monocytes/macrophages), and JM 1 (pre-B cell lymphoma) all showed greater expression of GHRH mRNA relative to PBMC. However, two cell lines, CCRF-SB, a B lymphoblastoid cell line, and HL-60, a promyelocytic cell line, expressed GHRH mRNA at similar levels as PBMC.

A significant decrease in the percentage of lymphocytes (CD45⁺ cells) expressing GHRH protein was found in age-advanced men and women compared with young men and women. This decline was noted in B cells (CD20⁺) and monocytes (CD14⁺), but not in T cells (CD3⁺). GHRH mRNA expression in PBMC derived from postmenopausal women was lower than that from premenopausal women. However, no differences in PBMC GHRH mRNA expression were found in young and old men. Although in older men there were fewer peripheral lymphocytes that express GHRH protein, these cells secreted significantly more GHRH in vitro than cells from postmenopausal women with no hormone replacement therapy (HRT), but similar levels as cells from women receiving HRT. PBMC from women receiving HRT secreted more GHRH in vitro than cells from women receiving no hormone replacement.

This study demonstrates that the expression of immune GHRH is dynamic, and therefore likely to be regulated. Increased expression of GHRH in certain immune tumors suggests that GHRH may be mitogenic under certain conditions and therefore play a role in the pathogenesis of select immune cell tumors. Collectively, these results suggest a role for GHRH as a local immune modulator and in the pathophysiology of immunosenescence and immune cell tumors.

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