The study was undertaken to assess the effects of ovarian hormone withdrawal in prepubertal age on thymopoiesis in 2- (young) and 11-month-old (middle-aged) rats. In ovariectomized (Ox) rats, irrespective of age, thymic weight and cellularity were greater than in age-matched controls, but the values of both parameters exhibited the age-related decline. In addition, although thymopoietic efficiency was increased in both groups of Ox rats when compared with age-matched controls, thymopoiesis exhibited the age-related decline mirrored in the lower numbers of both CD4+ and CD8+ recent thymic emigrants in peripheral blood. This reflected the prethymic changes affecting bone marrow progenitor generation/entry and the thymic alterations encompassing the impaired progenitor progression through early pre-T-cell receptor developmental stages (defined by CD45RC/CD2 expression) and, possibly, a more pronounced decrease in the proliferation of the most mature thymocytes. Apart from the changes at thymocyte level, in Ox rats the age-related alterations in thymic stroma (substantiated in a prominent loss of thymic epithelial cells) were registered. Ovariectomy-induced changes in thymic lymphoid and epithelial component, most probably, influenced each other leading to the increase in thymic expression of interleukin-6 and interleukin-7 mRNAs along with time after ovariectomy. Collectively, the study showed that the withdrawal of ovarian hormones in prepubertal age increases the efficiency of thymopoiesis in young adult rats, but does not prevent decline in thymopoiesis occurring with age.
LawDASpruytLLPatersonDJWilliamsAF. Subsets of thymopoietic rat thymocytes defined by expression of the CD2 antigen and the MRC OX-22 determinant of the leukocyte-common antigen CD45. Eur J Immunol1989; 19: 2289–95.
2.
HünigTTorres-NagelNMehlingBParkHJHerrmannT. Thymic development and repertoire selection: the rat perspective. Immunol Rev2001; 184: 7–19.
3.
ZamoyskaRLovattM. Signalling in T-lymphocyte development: integration of signaling pathways is the key. Curr Opin Immunol2004; 16: 191–6.
4.
AspinallRAndrewD. Thymic involution in aging. J Clin Immunol2000; 20: 250–6.
5.
BerzinsSPUldrichAPSutherlandJSGillJMillerJFGodfreyDIBoydRL. Thymic regeneration: teaching an old immune system new tricks. Trends Mol Med2002; 8: 469–76.
6.
AwDSilvaABMaddickMvon ZglinickiTPalmerDB. Architectural changes in the thymus of aging mice. Aging Cell2008; 7: 158–67.
7.
TaubDDLongoDL. Insights into thymic aging and regeneration. Immunol Rev2005; 205: 72–93.
8.
AwDSilvaABPalmerDB. Immunosenescence: emerging challenges for an ageing population. Immunology2007; 120: 435–46.
9.
GoldbergGLZakrzewskiJLPeralesMAvan den BrinkMR. Clinical strategies to enhance T cell reconstitution. Semin Immunol2007; 19: 289–96.
10.
LeposavićGPerišićM. Age-associated remodeling of thymopoiesis: role for gonadal hormones and catecholamines. Neuroimmunomodulation2008; 15: 290–322.
11.
GrossmanCJ. Interactions between the gonadal steroids and the immune system. Science1985; 227: 257–61.
12.
UtsuyamaMHirokawaK. Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy. Mech Ageing Dev1989; 47: 175–85.
13.
BodeyBBodeyBJrSiegelSEKaiserHE. Involution of the mammalian thymus, one of the leading regulators of aging. In Vivo1997; 11: 421–40.
14.
KuhlHGrossMSchneiderMWeberWMehlisWStegmullerMTaubertHD. The effect of sex steroids and hormonal contraceptives upon thymus and spleen on intact female rats. Contraception1983; 28: 587–601.
15.
LusterMIHayesHTKorachKTuckerANDeanJHGreenleeWF. Estrogen immunosuppression is regulated through estrogenic responses in the thymus. J Immunol1984; 133: 110–6.
16.
WindmillKFMeadeBJLeeVW. Effect of prepubertal gonadectomy and sex steroid treatment on the growth and lymphocyte populations of the rat thymus. Reprod Fertil Dev1993; 5: 73–81.
17.
OnerHOzanE. Effects of gonadal hormones on thymus gland after bilateral ovariectomy and orchidectomy in rats. Arch Androl2002; 48: 115–26.
18.
YellayiSNaazASzewczykowskiMASatoTWoodsJAChangJSegreMAllredCDHelferichWGCookePS. The phytoestrogen genistein induces thymic and immune changes: a human health concern?Proc Natl Acad Sci USA2002; 99: 7616–21.
19.
BlackerCMAtayaKMSavoy-MooreRTSubramanianMGMutchnicMGDunbarJC. The gonadotropin-releasing hormone agonist leuprolide affects the thymus and other non-reproductive systems of female rats. Acta Endocrinol1991; 125: 581–9.
20.
LeposavićGKarapetrovićBObradovićSVidić-DankovićBKosecD. Differential effects of gonadectomy on the thymocyte phenotypic profile in male and female rats. Pharmacol Biochem Behav1996; 54: 269–76.
21.
MinHMontecino-RodriguezEDorshkindK. Reassessing the role of growth hormone and sex steroids in thymic involution. Clin Immunol2006; 118: 117–23.
22.
MaffucciJAGoreACAge-related changes in hormones and their receptors. In: ConnPM (ed.) Handbook of Models for Human Aging, Burlington, San Diego, London: Elsevier Academic Press, 2006, pp. 533–51.
23.
FletcherAReisegerJVlahosKSeachNDudakovJChidgeyABoydAThymic regeneration in mice and humans following sex steroid ablation. In: FülöpTFranceschiCHirokawaKPawelecG (eds). Handbook on Immunosenescence: Basic Understanding and Clinical Applications, Dordrecht, Netherlands: Springer Science, 2009, pp. 1572–609.
24.
RaoLVClevelandRPKimmelRJAtayaKM. Gonadotropin-releasing hormone agonist influences absolute levels of lymphocyte subsets in vivo in male mice. Immunol Cell Biol1996; 74: 134–43.
25.
LynchHEGoldbergGLChidgeyAVan den BrinkMRMBoydRSempowskiGD. Thymic involution and immune reconstitution. Trends Immunol2009; 30: 366–73.
26.
TsengYLWubMHYangHCWangCYLinCF. Autocrine IL-6 regulates GRO-a production in thymic epithelial cells. Cytokine2010; 51: 195–201.
27.
LePTLazorickSWhichardLPYangYCClarkSCHaynesBFSingerKH. Human thymic epithelial cells produce IL-6, granulocyte-monocyte-CSF, and leukemia inhibitory factor. J Immunol1990; 145: 3310–5.
28.
ČolićMPejnovićNKataranovskiMStojanovićNTerzićTDujićA. Rat thymic epithelial cells in culture constitutively secrete IL-1 and IL-6. Int Immunol1991; 3: 1165–74.
29.
AlvesNLRichard-Le GoffOHuntingtonNDSousaAPRibeiroVSGBordackAVivesFLPedutoLChidgeyACumanoABoydREberlGDi SantoJP. Characterization of the thymic IL-7 niche in vivo. PNAS2009; 106: 1512–7.
30.
PeschonJJMorrisseyPJGrabsteinKHRamsdellFJMaraskovskyEGliniakBCParkLSZieglerSFWilliamsDEWareCBMeyerJDDavisonBL. Early lymphocyte expansionis severely impaired in interleukin 7 receptor-deficient mice. J Exp Med1994; 180: 1955–60.
31.
YamashitaINagataTTadaTNakayamaT. CD69 cell surface expression identifies developing thymocytes which audition for T cell antigen receptor-mediated positive selection. Int Immunol1993; 5: 1139–50.
32.
SwatWDessingMvon BoehmerHKisielowP. CD69 expression during selection and maturation of CD4+8+ thymocytes. Eur J Immunol1993; 23: 739–46.
33.
HueberAOBernardAMBattariCLMarguetDMassolPFoaCBrunNGarciaSStewartCPierresMHeHT. Thymocytes in Thy-1-/- mice show augmented TCR signaling and impaired differentiation. Curr Biol1997; 7: 705–8.
34.
SeddonBMasonD. The third function of the thymus. Immunol Today2000; 21: 95–9.
35.
HoriSNomuraTSakaguchiS. Control of regulatory T cell development by the transcription factor Foxp3. Science2003; 299: 1057–61.
36.
BerzinsSPUldrichAPPellicciDGMcNabFHayakawaYSmythMJGodfreyDI. Parallels and distinctions between T and NKT cell development in the thymus. Immunol Cell Biol2004; 82: 269–75.
37.
FrasorJBarnettDHDanesJMHessRParlowAFKatzenellenbogenBS. Response-specific and ligand dose-dependent modulation of estrogen receptor (ER) alpha activity by ERbeta in the uterus. Endocrinology2003; 44: 3159–66.
38.
BoehmTScheuSPfefferKBleulCC. Thymic medullary epithelial cell differentiation, thymocyte emigration, and the control of autoimmunity require lympho-epithelial cross talk via LTbetaR. J Exp Med2003; 198: 757–69..
39.
XiHKershG. Early growth response gene 3 regulates thymocyte proliferation during the transition from CD4−CD8− to CD4+CD8+. J Immunol2004; 172: 964–71.
40.
WatsonJVChambersSHSmithPJ. A pragmatic approach to the analysis of DNA histograms with a definable G1 peak. Cytometry1987; 8: 1–8.
41.
GogalRMJrSmithBJKalnitskyJHolladaySD. Analysis of apoptosis of lymphoid cells in fish exposed to immunotoxic compounds. Cytometry2000; 39: 310–8.
42.
TibbettsTADeMayoFRichSConneely OM’ O'MalleyBW. Progesterone receptors in the thymus are required for thymic involution during pregnancy and for normal fertility. Proc Natl Acad Sci USA1999; 96: 12021–6.
43.
ZajchowskiSHoffman-GoetzL. Supraphysiological level of estrogen exposure in vivo increases lymphoid cell death in mice. Life Sci2000; 66: 1451–9..
44.
CalemineJBGogalRMJrLengiASponenbergPAhmedSA. Immunomodulation by diethylstilbestrol is dose and gender related: effects on thymocyte apoptosis and mitogen-induced proliferation. Toxicology2002; 178: 101–18..
45.
YaoGHouY. Thymic atrophy via estrogen-induced apoptosis is related to Fas/FasL pathway. Int Immunopharmacol2004; 4: 213–21..
46.
BrunelliRFrascaDBachieriSSpanòMFattorossiAMosielloLFD'AmelioRZichellaLDoriaG. Changes in thymocyte subsets induced by estradiol administration or pregnancy. Ann N Y Acad Sci1992; 650: 109–14.
47.
ZollerALSchnellFJKershGJ. Murine pregnancy leads to reduced proliferation of maternal thymocytes and decreased thymic emigration. Immunology2007; 121: 207–15..
48.
SakabeKKawashimaIUranoRSeikiKItohT. Effects of sex steroids on the proliferation of thymic epithelial cells in a culture model: a role of protein kinase C. Immunol Cell Biol1994; 72: 193–9.
49.
Zhao H, Tian Z, Hao J, Chen B. Extragonadal aromatization increases with time after ovariectomy in rats. Reprod Biol Endocrinol Epub ahead of print 2005. DOI: 10.1186/1477-7827-3-6.
50.
MartinAAlonsoLMGomez del MoralMZapataAG. Ultrastructural changes in the adult rat thymus after estradiol benzoate treatment. Tissue Cell1994; 26: 169–79.
51.
HuangHPatelDDMantonKG. The immune system in aging: roles of cytokines, T cells and NK cells. Front Biosci2005; 10: 192–215.
AndrewDAspinallR. IL-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J Immunol2001; 166: 1524–30.
54.
ZubkovaIMostowskiHZaitsevaM. Tissue chemokine gene expression in the stromal cells in response to thymocyte depletion: implication for thymus reconstitution. J Immunol2005; 175: 2321–30.
55.
ZollerALKershGJ. Estrogen induces thymic atrophy by eliminating early thymic progenitors and inhibiting proliferation of beta-selected thymocytes. J Immunol2006; 176: 7371–8.
ShortmanKVremecDEgertonM. The kinetics of T cell antigen receptor expression by subgroups of CD4+8+ thymocytes: delineation of CD4+8+3(2+) thymocytes as post-selection intermediates leading to mature T cells. J Exp Med1991; 173: 323–32.
58.
PilipovićIVidić-DankovićBPerišićMRadojevićKČolićMTodorovićVLeposavićG. Sexual dimorphism in the catecholamine-containing thymus microenvironment: a role for gonadal hormones. J Neuroimmunol2008; 195: 7–20.
59.
Wajeman-ChaoSALancasterSAGrafLHJrChambersD. Mechanism of catecholamine-mediated destabilization of messengerRNA encoding Thy-1 protein in T-lineage cells. J Immunol1998; 161: 4825–33.
60.
ScrepantiIMorroneSMecoDSantoniAGulinoAPaoliniRCrisantiAMathiesonBJFratiL. Steroid sensitivity of thymocyte subpopulations during intrathymic differentiation. Effects of 17 beta-estradiol and dexamethasone on subsets expressing T cell antigen receptor or IL-2 receptor. J Immunol1989; 142: 3378–83.
61.
FontenotJDRudenskyAY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol2005; 6: 331–7.
62.
PorubskySSpeakAOLuckowBCerundoloVPlattFMGroneHJ. Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide (iGb3) deficiency. PNAS2007; 104: 5977–82.
63.
MatsuuraAKinebuchiMChenHZKatabamiSShimizuTHashimotoYKikuchiKSatoN. NKT cells in the rat: organ-specific distribution of NK T cells expressing distinct Vα14 chains. J Immunol2000; 164: 3140–8.
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