title: The immune-endocrine loop during aging: role of growth hormone and insulin-like growth factor-I.
abstract: Why a primary lymphoid organ such as the thymus involutes during aging remains a fundamental question in immunology. Aging is associated with a decrease in plasma growth hormone (somatotropin) and IGF-I, and this somatopause of aging suggests a connection between the neuroendocrine and immune systems. Several investigators have demonstrated that treatment with either growth hormone or IGF-I restores architecture of the involuted thymus gland by reversing the loss of immature cortical thymocytes and preventing the decline in thymulin synthesis that occurs in old or GH-deficient animals and humans. The proliferation, differentiation and functions of other components of the immune system, including T and B cells, macrophages and neutrophils, also demonstrate age-associated decrements that can be restored by IGF-I. Knowledge of the mechanism by which cytokines and hormones influence hematopoietic cells is critical to improving the health of aged individuals. Our laboratory has recently demonstrated that IGF-I prevents apoptosis in promyeloid cells, which subsequently permits these cells to differentiate into neutrophils. We also demonstrated that IL-4 acts much like IGF-I to promote survival of promyeloid cells and to activate the enzyme phosphatidylinositol 3'-kinase (PI 3-kinase). However, the receptors for IGF-I and IL-4 are completely different, with the intracellular beta chains of the IGF receptor possessing intrinsic tyrosine kinase activity and the alpha and gammac subunit of the heterodimeric IL-4 receptor utilizing the Janus kinase family of nonreceptor protein kinases to tyrosine phosphorylate downstream targets. Both receptors share many of the components of the PI 3-kinase signal transduction pathway, converging at the level of insulin receptor substrate-1 or insulin receptor subtrate-2 (formally known as 4PS, or IL-4 Phosphorylated Substrate). Our investigations with IGF-I and IL-4 suggest that PI 3-kinase inhibits apoptosis by maintaining high levels of the anti-apoptotic protein Bcl-2. The sharing of common activation molecules, despite vastly different protein structures of their receptors, forms a molecular explanation for the possibility of cross talk between IL-4 and IGF-I in regulating many of the events associated with hematopoietic differentiation, proliferation and survival.
authors.affiliation: Laboratory of Immunophysiology, Department of Animal Sciences, University of Illinois, Urbana, Ill., USA.
authors.forename: W
authors.initials: W
authors.lastname: Burgess
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: Q
authors.initials: Q
authors.lastname: Tang
authors.forename: A
authors.initials: A
authors.lastname: Ozawa
authors.forename: R
authors.initials: R
authors.lastname: VanHoy
authors.forename: S
authors.initials: S
authors.lastname: Arkins
authors.forename: R
authors.initials: R
authors.lastname: Dantzer
authors.forename: K W
authors.initials: KW
authors.lastname: Kelley
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology; D002454:Cell Differentiation; D013006:Growth Hormone / Q000502:physiology*; D006410:Hematopoiesis; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010903:Pituitary Gland, Anterior / Q000502:physiology; D019948:Receptors, Interleukin-4 / Q000502:physiology; D013950:Thymus Gland / Q000502:physiology
chemical_list: D019948:Receptors, Interleukin-4; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases