Growth Hormone Modulates Thymocyte Development in Vivo through a Combined Action of Laminin and CXC Chemokine Ligand 12

Smaniotto, Salete; Coelho, Valéria de Mello; Villa‐Verde, Déa Maria Serra; Pleau, Jean-Marie; Postel-Vinay, Marie-Catherine; Dardenne, Mireille; Savino, Wilson

doi:10.1210/en.2004-0709

Cited by 61 publications

(89 citation statements)

References 31 publications

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“…This was seen in both C57/BL6 and NOD thymocytes. Interestingly, it has also been reported in growth hormone transgenic mice, as well as in BALB/c mice infected with the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas' disease (16,17).…”

Section: Discussionmentioning

confidence: 90%

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Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Mendes-da-Cruz

Smaniotto

Keller

et al. 2008

The Journal of Immunology

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We previously described a fibronectin/VLA-5-dependent impairment of NOD thymocyte migration, correlated with partial thymocyte arrest within thymic perivascular spaces. Yet, NOD thymocytes still emigrate, suggesting the involvement of other cell migration-related alterations. In this context, the aim of this work was to study the role of extracellular matrix ligands, alone or in combination with the chemokine CXCL12, in NOD thymocyte migration. Intrathymic contents of CXCL12, fibronectin, and laminin were evaluated by immunohistochemistry while the expression of corresponding receptors was ascertained by flow cytometry. Thymocyte migration was measured using Transwell chambers and transendothelial migration was evaluated in the same system, but using an endothelial cell monolayer within the chambers. NOD thymocytes express much lower VLA-5 than C57BL/6 thymocytes. This defect was particularly severe in CD4+ thymocytes expressing Foxp3, thus in keeping with the arrest of Foxp3+ cells within the NOD giant perivascular spaces. We observed an enhancement in CXCL12, laminin, and fibronectin deposition and colocalization in the NOD thymus. Furthermore, we detected altered expression of the CXCL12 receptor CXCR4 and the laminin receptor VLA-6, as well as enhanced migratory capacity of NOD thymocytes toward these molecules, combined or alone. Moreover, transendothelial migration of NOD thymocytes was diminished in the presence of exogenous fibronectin. Our data unravel the existence of multiple cell migration-related abnormalities in NOD thymocytes, comprising both down- and up-regulation of specific responses. Although remaining to be experimentally demonstrated, these events may have consequences on the appearance of autoimmunity in NOD mice.

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Section: Discussionmentioning

confidence: 90%

“…Cells were washed and maintained in PBS-5% FCS for cell counting and subsequently submitted to four-or six-color immunofluorescence staining as previously described (16). Cells were then evaluated by flow cytometry in a FACSCalibur or FACSCanto II device (BD Biosciences).…”

Section: Cytofluorometrymentioning

confidence: 99%

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Mendes-da-Cruz

Smaniotto

Keller

et al. 2008

The Journal of Immunology

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“…Some reports indicate a role for GH as an immune response activator (5,20); we thus characterized immune cell populations in blood, spleen, and peripheral lymph nodes of NOD and NOD-Tg bGH mice. Flow cytometry analysis showed similar immune cell populations in both mouse lines (Table S1).…”

Section: Nod-tg Bgh Mice Have Normal Delayed Type Hypersensitivitymentioning

confidence: 99%

Growth hormone prevents the development of autoimmune diabetes

Villares

Kakabadse

Juarranz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Evidence supports a relationship between the neuroendocrine and the immune systems. Data from mice that overexpress or are deficient in growth hormone (GH) indicate that GH stimulates T and B-cell proliferation and Ig synthesis, and enhances maturation of myeloid progenitor cells. The effect of GH on autoimmune pathologies has nonetheless been little studied. Using a murine model of type 1 diabetes, a T-cell-mediated autoimmune disease characterized by immune cell infiltration of pancreatic islets and destruction of insulin-producing β-cells, we observed that sustained GH expression reduced prodromal disease symptoms and eliminated progression to overt diabetes. The effect involves several GH-mediated mechanisms; GH altered the cytokine environment, triggered anti-inflammatory macrophage (M2) polarization, maintained activity of the suppressor T-cell population, and limited Th17 cell plasticity. In addition, GH reduced apoptosis and/or increased the proliferative rate of β-cells. These results support a role for GH in immune response regulation and identify a unique target for therapeutic intervention in type 1 diabetes.beta cells | Tregs G rowth hormone (GH) is a pleiotropic hormone that affects a broad spectrum of physiological functions, from carbohydrate and lipid metabolism to the immune response (1). Several studies have linked GH with autoimmune diseases, although its effects on the immune system are still debated. Whereas some reports using GH-deficient mice indicate that it does not affect immune competence (2), others suggest that GH is necessary for correct immune system development (1, 3). The GH receptor (GHR) is expressed by several lymphocyte subpopulations (4). GH stimulates in vitro T and B-cell proliferation (5) and Ig synthesis (6); enhances human myeloid progenitor cell maturation (7); and modulates in vivo Th1/Th2 (8) and humoral immune responses (1). In addition, therapeutic activation of the GH/STAT5B axis is postulated as a target for restoring mucosal tolerance in Crohn disease (9, 10). A single point mutation in STAT5B limits its DNA binding activity as well as maintenance of FOXP3 expression by Treg cells in nonobese diabetic (NOD) mice (11). These mice develop type 1 diabetes, which is characterized by autoimmune destruction of pancreatic β-cells due to the effect of environmental factors on genetically predisposed individuals (12,13). Although this murine model does not completely mimic the human disease, most steps in the pathogenesis, including prodromal and clinical symptoms, are closely comparable (14).Despite the interdependence of GH and insulin regulation and the known effects of GH and insulin-like growth factor 1 (IGF1) on pancreatic β-cell survival, proliferation and neogenesis (15, 16), hormone influences have not been described in type 1 diabetes; no specific studies have addressed the consequences of long-term GH replacement therapy in this disease. Here we show the effects of long-term GH supplementation as a tool to modulate autoimmune attack on pancreatic β-cells. NOD...

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“…GH/IGF-1 could act on numerous thymic functions. Different studies on rodents have shown that the somatotrope axis act on thymocyte number [83,84], on TEC growth [85,86] and on the production by TEC of the chemokines CXCL12 and CCL25 [87,88].…”

Section: The Somatotrope Gh/igf-1 Axis and Thymus Function In Rodentsmentioning

confidence: 99%

“…As for HAARTtreated HIV infection, conjonction of thymotropism of pathogen, GH/IGF-1 axis disturbance and correlated effects on T immune system suggest that GH can be considered as an immunomodulating substance for boosting the T-cell system and controlling parasite replication, and a combination of GH with anti-infectious drugs could be a new therapeutic strategy to reduce the harmful effects of Chagas disease. However, it should be noted that GH increases CXCL12 expression and pre-T cell migration [88], one of the chemokine augmented after T. cruzi infection with proposed negative consequences. Therefore, cautions must be taken before to concluding that GH treatment would always increment the benefit-cost ratio.…”

Section: Implications For Chagas Diseasementioning

confidence: 99%

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

Goffinet¹,

Mottet²,

Kermani³

et al. 2011

IEMAMC

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Abstract:The thymus is the central lymphoid structure where T-cell differentiation takes place, and a crucial organ for the maintenance of homeostasis in the immune system. Thymopoiesis includes intrathymic proliferation of T-cell precursors, selection and output of both self-tolerant and competent effector T cells, as well as of natural regulatory T cells (nTreg). In the crosstalk between the neuroendocrine and immune systems, peptide hormones have been more and more implicated in immunomodulation for the last thirty years. The somatotrope growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis in particular has been repeatedly shown to play a major regulatory role upon thymus function and T-cell development. This review will focus on the important thymotropic properties of the somatotrope GH/IGF-1 axis, and will try to discriminate these properties in function of the endocrine or paracrine/autocrine pathways involved in their mediation. Most importantly, in light of an increasing number of recent studies, GH and IGF-1 now appear as novel therapeutic agents that could be used for enhancing thymopoiesis in different cases of immune deficiencies, including aging-related immune dysfunction.Keywords: Thymus, growth hormone (GH), insulin-like growth factors (IGFs), HIV, growth hormone deficiency (GHD), Chagas disease. GENERAL INTRODUCTIONThe thymus is now considered as a crucial organ for maintenance of immune system homeostasis and the central lymphoid organ where occurs the generation of self-tolerant and competent naive T cells, as well as self-antigen specific natural Treg cells [1,2]. However, for a long time, the thymus has been regarded as an endocrine gland. In addition, the thymus now appears as a privileged site where the endocrine and immune systems intimately interact.A permanent crosstalk exists between the neuroendocrine and immune systems [3][4][5][6]. In addition to the strong modulation of immunity by glucocorticoids and sexual steroids, other hormones have been more and more involved in immunomodulation. Indeed, the somatotrope GH/IGF-1 axis, as well as prolactin and thyroid hormones [7], were shown to play an important regulatory role in T-cell development [8][9][10].GH is mainly synthesised in the anterior pituitary gland but can also be produced by immune cells [11,12]. GH has several biological actions in the immune system including regulation of thymopoiesis and T-cell development [13]. Nevertheless, it is uneasy to distinguish whether the thymotropic effects of GH are direct or mediated by IGF-1, as most *Address correspondence to this author at the University of Liege Center of Immunoendocrinology (CIL), Institute of Pathology CHU-B23, B-4000 Liege-Sart Tilman, Belgium; Tel: +32 43 66 25 50; Fax: +32 43 66 98 59; E-mail: vgeenen@ulg.ac.be of GH effects are driven by induction of IGF-1 and as IGF-1 has also been described as an endogenous factor in the thymic microenvironment [12]. The evolution of the research field has brought new insights that justify an overview update as some ancie...

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Growth Hormone Modulates Thymocyte Development in Vivo through a Combined Action of Laminin and CXC Chemokine Ligand 12

Cited by 61 publications

References 31 publications

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Multivectorial Abnormal Cell Migration in the NOD Mouse Thymus

Growth hormone prevents the development of autoimmune diabetes

Impact of the Somatotrope Growth Hormone (GH)/Insulin-Like Growth Factor 1 (IGF-1) Axis Upon Thymus Function: Pharmacological Implications in Regeneration of Immune Functions

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