The Anti-apoptotic Effect of Ghrelin on Restraint Stress- Induced Thymus Atrophy in Mice
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Thymic atrophy is a complication that results from exposure to many environmental stressors, disease treatments, and microbial challenges. Such acute stress-associated thymic loss can have a dramatic impact on the host’s ability to replenish the necessary naïve T cell output to reconstitute the peripheral T cell numbers and repertoire to respond to new antigenic challenges. We have previously reported that treatment with the orexigenic hormone ghrelin results in an increase in the number and proliferation of thymocytes after dexamethasone challenge, suggesting a role for ghrelin in restraint stress-induced thymic involution and cell apoptosis and its potential use as a thymostimulatory agent. In an effort to understand how ghrelin suppresses thymic T cell apoptosis, we have examined the various signaling pathways induced by receptor-specific ghrelin stimulation using a restraint stress mouse model. In this model, stress-induced apoptosis in thymocytes was effectively blocked by ghrelin. Western blot analysis demonstrated that ghrelin prevents the cleavage of pro-apoptotic proteins such as Bim, Caspase-3, and PARP. In addition, ghrelin stimulation activates the Akt and Mitogen-activated protein kinases (MAPK) signaling pathways in a time/dosedependent manner. Moreover, we also revealed the involvement of the FoxO3a pathway in the phosphorylation of Akt and ERK1/2. Together, these findings suggest that ghrelin inhibits apoptosis by modulating the stress-induced apoptotic signal pathway in the restraint-induced thymic apoptosis.
Abstract
Thymic atrophy is a complication that results from exposure to many environmental stressors, disease treatments, and microbial challenges. Such acute stress-associated thymic loss can have a dramatic impact on the host’s ability to replenish the necessary naïve T cell output to reconstitute the peripheral T cell numbers and repertoire to respond to new antigenic challenges. We have previously reported that treatment with the orexigenic hormone ghrelin results in an increase in the number and proliferation of thymocytes after dexamethasone challenge, suggesting a role for ghrelin in restraint stress-induced thymic involution and cell apoptosis and its potential use as a thymostimulatory agent. In an effort to understand how ghrelin suppresses thymic T cell apoptosis, we have examined the various signaling pathways induced by receptor-specific ghrelin stimulation using a restraint stress mouse model. In this model, stress-induced apoptosis in thymocytes was effectively blocked by ghrelin. Western blot analysis demonstrated that ghrelin prevents the cleavage of pro-apoptotic proteins such as Bim, Caspase-3, and PARP. In addition, ghrelin stimulation activates the Akt and Mitogen-activated protein kinases (MAPK) signaling pathways in a time/dosedependent manner. Moreover, we also revealed the involvement of the FoxO3a pathway in the phosphorylation of Akt and ERK1/2. Together, these findings suggest that ghrelin inhibits apoptosis by modulating the stress-induced apoptotic signal pathway in the restraint-induced thymic apoptosis.
참고문헌 (29)
- Steinmann, G. G, "Changes in the human thymus during aging", Curr. Top. Pathol, 75, pp.43~88 (1986)
- Taub, D. D, "Rejuvenation of the aging thymus: growth hormone-mediated and ghrelin-mediated signaling pathways", Curr. Opin. Pharmacol, 10, pp.408~424 (2010)
- Berczi, I, "Neuroimmune regulation in immunocompetence, acute illness, and healing", Ann. N. Y. Acad. Sci, 1153, pp.220~239 (2009)
- Gruver, A. L, "Cytokines, leptin, and stress-induced thymic atrophy", J. Leukoc. Biol, 84, pp.915~923 (2008)
- Billard, M. J, "Acute endotoxin-induced thymic atrophy is characterized by intrathymic inflammatory and wound healing responses", PLoS One, 6, pp.e17940~ (2011)
- Wang, S. D, "Sepsis-induced apoptosis of the thymocytes in mice", J. Immunol, 152, pp.5014~5021 (1994)
- Lee, J. H, "Ghrelin augments murine T-cell proliferation by activation of the phosphatidylinositol-3-kinase, extracellular signal-regulated kinase and protein kinase C signaling pathways.", FEBS Lett, 588, pp.4708~4719 (2014)
- Baatar, D, "The effects of ghrelin on inflammation and the immune system", Mol. Cell. Endocrinol, 340, pp.44~58 (2011)
- Prodam, F, "Ghrelin gene products in acute and chronic inflammation", Arch. Immunol. Ther. Exp. (Warsz.), 62, pp.369~384 (2014)
- DeBoer, M. D, "The use of ghrelin and ghrelin receptor agonists as a treatment for animal models of disease: efficacy and mechanism", Curr. Pharm. Des, 18, pp.4779~4799 (2012)
- Lee, J. H, "Tellurium compound AS101 ameliorates experimental autoimmune encephalomyelitis by VLA-4 inhibition and suppression of monocyte and T cell infiltration into the CNS", Neuromolecular Med, 16, pp.292~307 (2014)
- Tesauro, M, "Cardiovascular and metabolic effects of ghrelin", Curr. Diabetes Rev, 6, pp.228~235 (2010)
- Zhang, G. G, "Ghrelin protects heart against ERS-induced injury and apoptosis by activating AMP-activated protein kinase", Peptides, 48, pp.156~165 (2013)
- Baldelli, R, "Ghrelin: a new hormone with endocrine and nonendocrine activities", Pediatr. Endocrinol. Rev, 2, pp.8~14 (2004)
- Veldhuis, J. D, "Integrating GHS into the Ghrelin System", Int. J. Pept (2010)
- Dixit, V. D, "Ghrelin promotes thymopoiesis during aging", J.Clin.Invest, 117, pp.2778~2790 (2007)
- El-Missiry, M. A, "Antioxidant Enzyme", pp.303~320 (2012), InTech
- Huang, H, "FOXO factors: a matter of life and death", Future Oncol, 2, pp.83~89 (2006)
- Huang, H, "Dynamic FoxO transcription factors", J. Cell Sci, 120, pp.2479~2487 (2007)
- Burgering, B. M, "Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB", Akt is off duty, 2003, pp.73, 689~701
- GHRP-6 serves as CCR5 chemokine receptor antagonist, "Int. J. Med. Sci", 2012, 51~58
- Baldanzi, G, "Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1", 2 and PI 3-kinase, J. Cell Biol, pp.2002, 159[DOI]
- Granata, R, "Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate", protein kinase A, extracellular signalregulated kinase 1, Akt signaling, pp.Endocrinology, 2007[DOI]
- Kim, M. S, "The mitogenic and antiapoptotic actions of ghrelin in 3T3-L1 adipocytes", Mol. Endocrinol, 18, pp.2291~2301 (2004)
- Chung, H, "Phosphatidylinositol-3-kinase", Akt, 2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivationinduced apoptosis in primary rat cortical neuronal cells, pp.J. Endocrinol, 2008[DOI]
- Bonfili, L, "Ghrelin induces apoptosis in colon adenocarcinoma cells via proteasome inhibition and autophagy induction", Apoptosis, 18, pp.1188~1200 (2013)
- Conconi, M. T, "Ghrelin inhibits FGF-2-mediated angiogenesis in vitro and in vivo", Peptides, 25, pp.2179~2185 (2004)
- Lam, E. W, "Forkhead box proteins: tuning forks for transcriptional harmony", Nat. Rev. Cancer, 13, pp.482~495 (2013)
- Dong, S, "14-3-3 Integrates prosurvival signals mediated by the AKT and MAPK pathways in ZNF198-FGFR1-transformed hematopoietic cells", Blood, 110, pp.360~369 (2007)