Growth hormone prevents the development of autoimmune diabetes

Abstract

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...

Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice

“…GHRH stimulates the release of GH from the pituitary; however the function of the GH/IGF1 axis in the causes and development of diabetes is complex (41)(42)(43). Sustained expression of GH prevents the development of autoimmune diabetes in NOD mice by modification of immune response (44). In our current study we did not observe elevated serum GH or IGF1 levels in diabetic mice after administration of MR-409 for 3 wk.…”

The beneficial effect of growth hormone treatment on islet mass in streptozotocin‐treated mice

“…All these studies support the results of our present study. Recently, it was demonstrated that GH prevents the development of T1D, in non‐obese diabetic (NOD) mice that overexpress bovine GH, apparently through an immunological effect of GH . Treatment with GH‐releasing hormone both in vitro in the NIS‐1 cell line and in vivo in streptozotocin‐induced diabetic NOD‐severe combined immunodeficiency mice after pancreatic transplantation demonstrated reduced islet cell apoptosis and normoglycemia .…”

Growth hormone treatment of premature ovarian failure in a mouse model via stimulation of the Notch-1 signaling pathway

“…Growth hormone (GH) is a pleiotropic hormone that affects a broad spectrum of physiological functions, from carbohydrate and lipid metabolism to immune response ( 10 – 16 ). Several previous studies have used GH to treat autoimmune diseases and POF.…”