Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Zhang, Yizhi; Chen, Zhoujia; Luo, Xiao‐Zhu; Wu, Bing; Li, Bin; Wang, Bin

doi:10.1080/21645515.2016.1191719

Cited by 25 publications

(20 citation statements)

References 30 publications

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“…In line with our findings, Li X revealed that RU486‐induced abortion was partially due to the reduced Foxp3 . Cimetidine resulted in the downregulation of Foxp3 via E3 ligase Stub1‐mediated proteasomal degradation . We found that EL4 cells have shown a decrease in Foxp3 protein upon exposure to ESA.…”

Section: Discussionsupporting

confidence: 89%

Chinese 1 strain of Toxoplasma gondii excreted–secreted antigens negatively modulate Foxp3 via inhibition of the TGFßRII/Smad2/Smad3/Smad4 pathway

Chen

Huang

Zhu

et al. 2017

J Cellular Molecular Medi

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Toxoplasma gondii is an opportunistic intracellular parasite and is considered an important aetiological factor in the process of abortion, especially as occurs in early gestation. Chinese 1 strain of T. gondii is a dominant genotype prevalent in China. Although it is known that early foetal resorption triggered by RH strain of T. gondii is attributable to immune mechanisms rather than its direct effect in uterus, the underlying mechanism of the abortion caused by Chinese 1 strain remains unclear. This study was designed to investigate the effect of excreted–secreted antigens (ESA) of Chinese 1 strain of T. gondii on the expression of forkhead box transcription factor (Foxp3) as it pertains to early pregnancy and abortion. ESA caused a marked inhibition in the expression of Foxp3 both in vivo and in vitro. In addition, ESA negatively modulated Smad2 and Smad3 at the posttranslational level. Smad2 siRNA cooperated with ESA to further suppress the level of Foxp3. This inhibitory effect on Foxp3 expression was partially abrogated by overexpression of Smad2, Smad3 and Smad4. Additionally, ESA attenuated the expression of TGFßRII, whereas TGFßRII agonist could profoundly reversed the decreased Foxp3 triggered by ESA. Collectively, the findings suggested that ESA restricted Foxp3 expression by inhibiting TGFßRII/Smad2/Smad3/Smad4 signalling, ultimately resulting in abortion.

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Section: Discussionsupporting

confidence: 89%

Chinese 1 strain of Toxoplasma gondii excreted–secreted antigens negatively modulate Foxp3 via inhibition of the TGFßRII/Smad2/Smad3/Smad4 pathway

Chen

Huang

Zhu

et al. 2017

J Cellular Molecular Medi

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“…In some experiments, mice were provided with cimetidine (CMTD, 100 mg/kg·d) by means of intragastric administration for 7 days starting from the day of the final irradiation. It has been reported that CMTD has a radioprotective effect by antioxidation and immunomodulation 64,68,69 . All animal experiments were approved by the Animal Ethical Committee of Fudan University and all methods were carried out in accordance with the guidelines of animal welfare legislation.…”

Section: Methodsmentioning

confidence: 99%

Fractionated irradiation of right thorax induces abscopal damage on testes leading to decline in fertility

Zhang

Yao

Song

et al. 2019

Sci Rep

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Radiation-induced abscopal effect (RIAE) may influence radiotherapy efficiency. However, it is unknown whether RIAE triggers abnormal genetic consequence. We present a novel evidence that, when mice were given fractionated irradiation on right thorax, the ultrastructure of blood-testis barrier was damaged in company with apoptosis induction in testes, and the sperm number and vitality were drastically decreased so that both the fertility and the survival of their offspring were reduced. Protein microarray assay and hormone detection showed that some cytokines especially TNF-α, TGF-β and estradiol in the serum of irradiated mice increased to higher levels in consistent with abscopal damage, and this conditioned serum had toxic effect on TM4 cells in vitro. When the mice were fed with cimetidine, the above abscopal responses were significantly attenuated. This study demonstrates in the first time that the thoracic irradiation (Th-IR) induces structural and functional damage in the distal testes and further cause fertility decline of irradiated male mice, which may have important implications in the strategy development of radiotherapy in avoiding abnormal genetic consequence.

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“…Upon TCR stimulation, E3 ubiquitin ligase, Cbl-b, together with Stub1, targets Foxp3 for ubiquitylation and degradation; and a deficiency of Cbl-b can partially rescue defective development of thymic Treg cells in Cd28 −/− mice (140). Cimetidine (CIM) can promote immune responses, suppress Treg cell function via activation of PI3K-AKT-mTOR signaling and increase of Stub1-mediated degradation of Foxp3, respectively (141). As mentioned above, Foxp3 phosphorylation by NLK prevents its association with the STUB1 and increases Foxp3 protein stabilization (87).…”

Section: Post-translational Modifications Of Foxp3mentioning

confidence: 99%

Foxp3 Post-translational Modifications and Treg Suppressive Activity

et al. 2019

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Regulatory T cells (Tregs) are engaged in maintaining immune homeostasis and preventing autoimmunity. Treg cells include thymic Treg cells and peripheral Treg cells, both of which can suppress the immune response via multiple distinct mechanisms. The differentiation, proliferation, suppressive function and survival of Treg cells are affected by distinct energy metabolic programs. Tissue-resident Treg cells hold unique features in comparison with the lymphoid organ Treg cells. Foxp3 transcription factor is a lineage master regulator for Treg cell development and suppressive activity. Accumulating evidence indicates that the activity of Foxp3 protein is modulated by various post-translational modifications (PTMs), including phosphorylation, O-GlcNAcylation, acetylation, ubiquitylation and methylation. These modifications affect multiple aspects of Foxp3 function. In this review, we define features of Treg cells and roles of Foxp3 in Treg biology, and summarize current research in PTMs of Foxp3 protein involved in modulating Treg function. This review also attempts to define Foxp3 dimer modifications relevant to mediating Foxp3 activity and Treg suppression. Understanding Foxp3 protein features and modulation mechanisms may help in the design of rational therapies for immune diseases and cancer.

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Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells

Cited by 25 publications

References 30 publications

Chinese 1 strain of Toxoplasma gondii excreted–secreted antigens negatively modulate Foxp3 via inhibition of the TGFßRII/Smad2/Smad3/Smad4 pathway

Chinese 1 strain of Toxoplasma gondii excreted–secreted antigens negatively modulate Foxp3 via inhibition of the TGFßRII/Smad2/Smad3/Smad4 pathway

Fractionated irradiation of right thorax induces abscopal damage on testes leading to decline in fertility

Foxp3 Post-translational Modifications and Treg Suppressive Activity

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