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1.
Aging (Albany NY) ; 8(1): 158-77, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26830321

ABSTRACT

Excessive DNA damage can induce an irreversible cell cycle arrest, called senescence, which is generally perceived as an important tumour-suppressor mechanism. However, it is unclear how cells decide whether to senesce or not after DNA damage. By combining experimental data with a parameterized mathematical model we elucidate this cell fate decision at the G1-S transition. Our model provides a quantitative and conceptually new understanding of how human fibroblasts decide whether DNA damage is beyond repair and senesce. Model and data imply that the G1-S transition is regulated by a bistable hysteresis switch with respect to Cdk2 activity, which in turn is controlled by the Cdk2/p21 ratio rather than cyclin abundance. We experimentally confirm the resulting predictions that to induce senescence i) in healthy cells both high initial and elevated background DNA damage are necessary and sufficient, and ii) in already damaged cells much lower additional DNA damage is sufficient. Our study provides a mechanistic explanation of a) how noise in protein abundances allows cells to overcome the G1-S arrest even with substantial DNA damage, potentially leading to neoplasia, and b) how accumulating DNA damage with age increasingly sensitizes cells for senescence.


Subject(s)
Cell Proliferation , Cellular Senescence , DNA Damage , Fibroblasts/pathology , Cell Proliferation/radiation effects , Cells, Cultured , Cellular Senescence/radiation effects , Cyclin-Dependent Kinase 2/metabolism , Cyclin-Dependent Kinase Inhibitor p21/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Dose-Response Relationship, Radiation , Fibroblasts/metabolism , Fibroblasts/radiation effects , G1 Phase Cell Cycle Checkpoints , Humans , Models, Biological , Primary Cell Culture , RNA Interference , Signal Transduction , Time Factors , Transfection
2.
J Immunol ; 190(6): 2650-8, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23396945

ABSTRACT

Normal pregnancy is characterized by an early expansion of regulatory T cells (Tregs), which is known to contribute to fetal tolerance. However, mechanisms and factors behind Treg expansion are not yet defined. Recently, we proposed that the pregnancy hormone human chorionic gonadotropin (hCG) efficiently attracts human Tregs to trophoblasts, favoring their accumulation locally. In this study, we hypothesized that hCG not only acts as a chemoattractant of Tregs but also plays a central role in pregnancy-induced immune tolerance. Virgin, normal pregnant, and abortion-prone female mice were treated either with 10 IU/ml hCG or PBS at days 0, 2, 4, and 6 of pregnancy. The hCG effect on Treg frequency and cytokine secretion was determined in Foxp3(gfp) females. hCG impact on Treg suppressive capacity was studied in vitro. In vivo, we investigated whether hCG enhances Treg suppressive capacity indirectly by modulating dendritic cell maturation in an established mouse model of disturbed fetal tolerance. Application of hCG increased Treg frequency in vivo and their suppressive activity in vitro. In females having spontaneous abortions, hCG provoked not only an augmentation of Treg numbers, but also normalized fetal abortion rates. hCG-generated Tregs were fully functional and could confer tolerance when adoptively transferred. hCG also retained dendritic cells in a tolerogenic state that is likely to contribute to both Treg expansion and prevention of abortion. Our results position hCG in a novel, so far unknown role as modulator of immune tolerance during pregnancy.


Subject(s)
Chorionic Gonadotropin/physiology , Immune Tolerance/physiology , Pregnancy Proteins/physiology , Pregnancy/immunology , Animals , Cells, Cultured , Female , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Inbred DBA , Mice, Transgenic
3.
PLoS One ; 7(8): e42301, 2012.
Article in English | MEDLINE | ID: mdl-22900010

ABSTRACT

Regulatory T cells (Treg) play an important role in fetal protection. They expand during normal pregnancy and protect fetal antigens from maternal effector cells. Their effect is associated with the up-regulation of tolerance-associated molecules at the fetal-maternal interface. Among these, Heme Oxygenase-1 (HO-1, coded by Hmox1) is of special importance as its blockage correlates with increased abortion rates and its up-regulation positively affects pregnancy outcome. Here, we aimed to investigate whether the protective effect of Treg is mediated by HO-1 in a mouse model. HO-1 blockage by Zinc Protoporhyrin (ZnPPIX) abrogated the protective effect of Treg transfer. We found that HO-1 is important in maintaining maternal dendritic cells (DCs) in an immature state, which contributes to the expansion of the peripheral Treg population. This brings to light one essential pathway through which Treg mediates the semi-allogeneic fetus tolerance.


Subject(s)
Dendritic Cells/immunology , Dendritic Cells/metabolism , Enzyme Inhibitors/pharmacology , Heme Oxygenase-1/antagonists & inhibitors , Protoporphyrins/pharmacology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Abortion, Spontaneous/genetics , Abortion, Spontaneous/immunology , Abortion, Spontaneous/metabolism , Animals , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Female , Fetal Death/genetics , Fetal Death/immunology , Fetal Death/metabolism , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation/drug effects , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Immune Tolerance/genetics , Immune Tolerance/immunology , Inflammation Mediators/immunology , Inflammation Mediators/metabolism , Lymphocyte Activation/immunology , Male , Mice , Mice, Transgenic , Pregnancy , Pregnancy Outcome/genetics , T-Lymphocytes, Regulatory/drug effects
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