Immune Function in Transgenic Mice Overexpressing Growth Hormone (GH) Releasing Hormone, GH or GH Antagonist

Increasing evidence has placed hormones and neuropeptides among potent immunomodulators, in both health and disease. Herein, we focus on the effects of growth hormone (GH) upon the thymus. Exogenous GH enhances thymic microenvironmental cell-derived secretory products such as cytokines and thymic hormones. Moreover, GH increases thymic epithelial cell (TEC) proliferation in vitro, and exhibits a synergistic effect with anti-CD3 in stimulating thymocyte proliferation, which is in keeping with the data showing that transgenic mice overexpressing GH or GH-releasing hormone exhibit overgrowth of the thymus. GH also influences thymocyte traffic: it increases human T-cell progenitor engraftment into the thymus; augments TEC/thymocyte adhesion and the traffic of thymocytes in the lymphoepithelial complexes, the thymic nurse cells; modulates in vivo the homing of recent thymic emigrants, enhancing the numbers of fluroscein isothiocyanate (FITC) cells in the lymph nodes and diminishing them in the spleen. In keeping with the effects of GH upon thymic cells is the detection of GH receptors in both TEC and thymocytes. Additionally, data indicate that insulin-like growth factor (IGF)-1 is involved in several effects of GH in the thymus, including the modulation of thymulin secretion, TEC proliferation as well as thymocyte/TEC adhesion. This is in keeping with the demonstration of IGF-1 production and expression of IGF-1 by TEC and thymocytes. Also, it should be envisioned as an intrathymic circuitry, involving not only IGF-1, but also GH itself, as intrathymic GH expression is seen both in TEC and in thymocytes, and that thymocyte-derived GH could enhance thymocyte proliferation. Finally, the possibility that GH improve thymic functions, including thymocyte proliferation and migration, places this molecule as a potential therapeutic adjuvant in immunodeficiency conditions associated with thymocyte decrease and loss of peripheral T cells. The crosstalk between the neuroendocrine and the immune systems is now well-demonstrated. Similar ligands and receptors used by these systems allow the existence of a physiological intra-and intersystem communication circuitry, which seems to play a relevant role in homeostasis. Increasing evidence has placed hormones and neuropeptides among potent immunomodulators, in both health and disease (reviewed in [1±4]). More particularly, these molecules modulate the physiology of the thymus [5]. Herein, we focus on the effects of growth hormone (GH) upon the microenvironmental and the lymphoid compartments of the thymus. Nevertheless, before discussing such effects, it seems worthwhile to provide background data concerning the immunomodulatory function of GH, as well as the general features regarding the thymic microenvironment and its role upon intrathymic T-cell differentiation.

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“…1B. This is in keeping with data showing that transgenic mice overexpressing GH or GH-releasing hormone exhibit overgrowth of the thymus [33].…”

Section: Modulatory Effects Of Gh Upon Proliferation and Death Of Thysupporting

confidence: 84%

The Thymus Gland: a Target Organ for Growth Hormone

et al. 2002

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“…2), and all express elevated free radical processes (Venkatraman et al 1994; Yahya et al 1996). Elevating GH can also induce features of autoimmunity (Dialynas et al 1999; Ogueta et al 2000; Yap et al 1998). Generally, dwarf and dietary‐restricted rodents show reduced basal immunological activity, whereas those with elevated growth express increased immunological activation (Davila et al 1987; Dialynas et al 1999; Ogueta et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Growth negatively impacts the life span of mammals

Rollo

2002

Evolution and Development

256

174

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A negative intraspecific relationship between growth and longevity was proposed in the early 20th century. Indeed, stunting the growth of rodents by restricting their food dramatically extended life span. Subsequently, however, the hypothesis that growth exacerbates aging rates fell into disfavor. Contributing to this was (a) the establishment of a positive relationship between body size and longevity interspecifically, (b) purported antiaging impacts of growth hormone, and (c) the fact that the longevity of even mature rodents that had completed growth was extended by dietary restriction. Furthermore, intraspecific analytical studies failed to provide any clear resolution. This article presents the first global analyses of maximal longevity versus maximum mature mass for laboratory rats and mice, based on a relatively comprehensive compilation of research across the 20th century. Peak body mass (which reflects juvenile growth rates) was negatively associated with longevity within both species. Proximal mechanisms for impacts of growth on longevity appear congruent with the free radical and immunological theories of aging.

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“…The enhancing effects of GH on thymocyte proliferation were first proposed when injections of GH3 (pituitary adenoma cells able to produce GH) to old rats were found to reverse age‐dependent thymic atrophy, with a consequent increase in thymocyte numbers 15. This finding was in keeping with data showing that transgenic mice overexpressing GH or GH‐releasing hormone exhibit overgrowth of the thymus 16. In fact, even when we normalize the number of thymocytes per gram of body weight, GH‐transgenic animals have higher thymocyte numbers than do the corresponding age/sex‐matched counterparts (Smaniotto et al , manuscript in preparation).…”

Section: Modulatory Effects Of Growth Hormone On Proliferation Of Thymentioning

confidence: 60%

In Vivo Effects of Growth Hormone on Thymic Cells

Savino

Smaniotto

Binart

et al. 2003

Annals of the New York Academy of Sciences

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Increasing evidence has placed the thymus as a target for neuroendocrine control. Herein we review the pleiotropic effects of growth hormone (GH) on this primary lymphoid organ, with emphasis on data derived from in vivo experiments. A series of results strongly indicate that GH enhances thymocyte proliferation in both rodents and humans. Moreover, in vivo treatment with GH enhances interleukin (IL)-6 production by mouse thymocytes, and ex vivo experiments show that production of other cytokines, such as IL-1 and GM-CSF, is also augmented. In a second vein, GH exerts a modulatory role on thymic hormone production, particularly the secretion of thymulin. In GH-treated animals as well as GH-transgenic mice, thymulin secretion is enhanced. In acromegalic patients we found higher levels of thymulin secretion, whereas the opposite was seen in dwarf mice and GH receptor knockout animals. Developing T cell migration is also under GH influence. Recombinant GH was found to increase human T cell engraftment in the thymus of SCID mice. Moreover, ex vivo thymocyte traffic into and out of thymic nurse cell complexes is enhanced after GH treatment. Lastly, we show that thymocyte export in vivo is modulated by GH, which favors the homing of CD4(+) recent thymic emigrants towards lymph nodes. In conclusion, the possibility that GH improves in vivo thymic functions, including thymocyte proliferation and migration, points to this molecule as a potential therapeutic adjuvant in T cell associated immunodeficiencies.

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Immune Function in Transgenic Mice Overexpressing Growth Hormone (GH) Releasing Hormone, GH or GH Antagonist

Cited by 16 publications

References 18 publications

The Thymus Gland: a Target Organ for Growth Hormone

The Thymus Gland: a Target Organ for Growth Hormone

Growth negatively impacts the life span of mammals

In Vivo Effects of Growth Hormone on Thymic Cells

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