The decline in adaptive immunity, T lymphocyte output and the contraction of the T cell receptor (TCR) repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of thymic progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic peptide hormone, ghrelin, and the anorexigenic hormone, leptin, are expressed by immune cells and regulate T-cell activation and inflammation. Our current work has demonstrated that both ghrelin and ghrelin receptor expression within the thymus diminishes with progressive aging. Infusion of ghrelin into old mice significantly improves the age-associated changes in thymic architecture and thymocyte counts with an increase in recent thymic emigrants (RTEs) and improvement of TCR diversity of peripheral CD4+ and CD8+ T cells. The ghrelin-induced thymopoiesis during aging was associated with enhancement of early thymocyte progenitors (ETP) and bone marrow-derived lineage negative sca-1, c-kit high (LSK) cell. Furthermore, the ghrelin and GHS-R deficient mice displayed enhanced age-associated thymic involution with reduced thymopoiesis and contraction of LSK hematopoietic stem cell compartment. The accelerated thymic involution observed in GHS-R knock out mice was reflected in major perturbations in the TCR repertoire of peripheral T lymphocyte subsets. Similarly, leptin infusion into old mice demonstrated similar effects on thymic progenitors and thymic involution as was observed with ghrelin and the pituitary hormone, growth hormone (GH). It appears that hormone-induced changes appear to be mediated via distinct signaling pathways. Our findings demonstrate a novel role for these hormones and their receptors in thymic biology and suggest a possible therapeutic benefit of harnessing these hormonal pathways in reconstitution of thymic function in elderly and in immunocompromised subjects. Moreover, we have found that these hormones modulate a variety of leukocyte functions and support the existence of a functional immunoregulatory network involving orexigenic and anorexigenic hormones in controlling immune cellular activation and differentiation, hematopoiesis and cell survival. Recent work has focused on the effects of these hormones on T-cell signaling and differentiation and the role of these hormones in the control of inflammatory cytokine signaling and activation. We believe these findings may provide valuable therapeutic interventional strategies by which we can control inflammation in various disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000758-11
Application #
7732317
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2008
Total Cost
$1,024,566
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Dixit, Vishwa D; Yang, Hyunwon; Cooper-Jenkins, Anthony et al. (2009) Reduction of T cell-derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation. Blood 113:5202-5
Singh, Udai P; Singh, Shailesh; Singh, Rajesh et al. (2008) CXCL10-producing mucosal CD4+ T cells, NK cells, and NKT cells are associated with chronic colitis in IL-10(-/-) mice, which can be abrogated by anti-CXCL10 antibody inhibition. J Interferon Cytokine Res 28:31-43
Kovac, Ilija P; Havlik, Richard J; Foley, Daniel et al. (2007) Linkage and association analyses of type 2 diabetes/impaired glucose metabolism and adiponectin serum levels in Japanese Americans from Hawaii. Diabetes 56:537-40
Dixit, Vishwa Deep; Yang, Hyunwon; Sun, Yuxiang et al. (2007) Ghrelin promotes thymopoiesis during aging. J Clin Invest 117:2778-90
Dixit, Vishwa Deep; Weeraratna, Ashani T; Yang, Hyunwon et al. (2006) Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. J Biol Chem 281:16681-90
Dixit, Vishwa Deep; Taub, Dennis D (2005) Ghrelin and immunity: a young player in an old field. Exp Gerontol 40:900-10
Taub, Dennis D; Longo, Dan L (2005) Insights into thymic aging and regeneration. Immunol Rev 205:72-93
Dixit, Vishwa Deep; Schaffer, Eric M; Pyle, Robert S et al. (2004) Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114:57-66
Dixit, Vishwa Deep; Sridaran, Rajagopala; Edmonsond, Megan A et al. (2003) Gonadotropin-releasing hormone attenuates pregnancy-associated thymic involution and modulates the expression of antiproliferative gene product prohibitin. Endocrinology 144:1496-505
Singh, Udai P; Singh, Shailesh; Taub, Dennis D et al. (2003) Inhibition of IFN-gamma-inducible protein-10 abrogates colitis in IL-10-/- mice. J Immunol 171:1401-6

Showing the most recent 10 out of 12 publications