The neuropeptides GnRH-II and GnRH-I are produced by human T cells and trigger laminin receptor gene expression, adhesion, chemotaxis and homing to specific organs

Abstract

Can T cells be directly activated to de novo gene expression by gonadotropin-releasing hormone-II (GnRH-II), a unique 10-amino-acid neuropeptide conserved through 500 million years of evolution? GnRH-II, which has been identified in mammals, shares 70% homology with the mammalian hypothalamic neurohormone GnRH (GnRH-I), the primary regulator of reproduction, but is encoded by a different gene. Although both neuropeptides are produced mainly in brain, their localization and promoter regulation differ, suggestive of distinct functions. Indeed, GnRH-II barely affects reproduction and its role in mammalian physiology is unknown. We find here that human normal and leukemic T cells produce GnRH-II and GnRH-I. Further, exposure of normal or cancerous human or mouse T cells to GnRH-II or GnRH-I triggered de novo gene transcription and cell-surface expression of a 67-kD non-integrin laminin receptor that is involved in cellular adhesion and migration and in tumor invasion and metastasis. GnRH-II or GnRH-I also induced adhesion to laminin and chemotaxis toward SDF-1alpha, and augmented entry in vivo of metastatic T-lymphoma into the spleen and bone marrow. Homing of normal T cells into specific organs was reduced in mice lacking GnRH-I. A specific GnRH-I-receptor antagonist blocked GnRH-I- but not GnRH-II-induced effects, which is suggestive of signaling through distinct receptors. We suggest that GnRH-II and GnRH-I, secreted from nerves or autocrine or paracrine sources, interact directly with T cells and trigger gene transcription, adhesion, chemotaxis and homing to specific organs, which may be of clinical relevance.

Differences in Hypercholesterolemia and Atherogenesis Induced by Common Androgen Deprivation Therapies in Male Mice

“…For more than a century it has been recognized that androgen deprivation affects the immune system,34 and the GnRH receptor has been found on immune cells from humans35, 36 and rodents 13, 37. Interestingly, stimulation of the GnRH receptor exacerbated lupus in castrated female mice14, 38 and treatment with GnRH receptor antagonist delayed the onset of autoimmune diabetes15 and increased the survival rate among lupus‐prone mice 14.…”

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…The manner in which local GnRH action modulates the physiology and patho-physiology of reproductive tissues is a focus of investigation [23,48,139]. More specialized roles in blastocyst implantation, physiological changes occurring during pregnancy, including modulation of the cellular immune system, and influences on reproductive and parental behavior are also regarded as possibilities in certain mammalian species [15,19,22,40,59,61]. Many mechanistic questions concerning the precise involvement of GnRH in such diverse processes remain unanswered.…”

Human Type II GnRH Receptor Mediates Effects of GnRH on Cell Proliferation

“…Moreover, in addition to the direct effects on gonads, it has been reported that GnRH may act as a neuromodulator or an immunomodulator. (Eisthen et al ., 2000;Oka, 2002;Ford et al ., 2003;Azad et al ., 1997;Enomoto et al ., 2001;Chen et al ., 2002). Although a number of studies have been performed on these effects of GnRH, little is known about the molecular mechanisms and physiological settings in which GnRH exerts its activities in extrapituitary tissues or organs.…”

“…These opposite effects of GnRH on cell proliferation are very interesting, but it has remained unknown whether GnRH has such activities in physiological settings, mainly because most previous studies were performed using cancer cell lines and pharmacological doses of GnRH. However, recently, the effects of GnRH on the cell proliferation of non-tumor cells, as well as on cell adhesion, cell migration, and cytoskeletal remodeling have been reported (Chen et al ., 2002;Romanelli et al ., 2004;Davidson et al ., 2004) and the physiological roles of the effects of GnRH on cell proliferation are being reconsidered.…”