Interferon gamma is involved in apoptosis of trophoblast cells at the maternal–fetal interface following Toxoplasma gondii infection

Zhang, Ling; Zhao, Mengnan; Jiao, Fang Wen; Xu, Xiaoyan; Liu, Xianbing; Jiang, Yuzhu; Zhang, Haixia; Ou, Xiaoxuan; Hu, Xuemei

doi:10.1016/j.ijid.2014.10.027

Cited by 33 publications

(38 citation statements)

References 34 publications

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“…Then, the local immune cells are the major source of IFNG in the maternal-fetal interface because the decidual natural killer cells, and consequently the trophoblast cells, are stimulated by IFNG in a paracrine manner. Decidual natural killer cells cocultured with trophoblast produce from 20 to 30 ng/ml IFNG, and this production increases significantly when these cells are infected by T. gondii (;80 ng/ml) [81]. Therefore, the IFNG concentrations used in our present study are similar to those found during in vivo conditions.…”

Section: Discussionsupporting

confidence: 79%

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

Barbosa

Lopes-Maria

Gomes

et al. 2015

Biology of Reproduction

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Considering that interleukin 10 (IL10), transforming growth factor beta1 (TGFB1), and interferon gamma (IFNG) are involved in the susceptibility of BeWo trophoblast cells to Toxoplasma gondii infection, the aim of the present study was to investigate the effector mechanisms triggered by these cytokines in the control of T. gondii in BeWo cells. For this purpose, infected/uninfected BeWo cells were treated with IL10, TGFB1 (50 ng/ml), and IFNG (20 or 100 ng/ml) in order to verify the phosphorylation of signal transducers and activators of transcription 1 (STAT1), STAT3, and Smad2, parasite intracellular proliferation, as well as the Th1/Th2/IL17A cytokine production. The treatment of BeWo cells with IL10 and TGFB1 favored T. gondii proliferation, and these findings were associated with STAT3 and Smad2 phosphorylation, respectively (P < 0.05). Also, these cytokine treatments were able to down-modulate TNF alpha (TNFA) and IL6 production (P < 0.05). Low concentration of IFNG was unable to control T. gondii infection but was able to trigger STAT1 phosphorylation and up-regulate IL6 and IL17A production; whereas a high concentration of IFNG was unable to activate STAT1 but down-modulated IL6 and TNFA and increased T. gondii proliferation (P < 0.05). IL10, TGFB1, and IFNG regulate a differential T. gondii proliferation in BeWo cells because they distinctly trigger intracellular signaling pathways and cytokine production, especially IL6 and TNFA. Our data open new windows to understand the mechanisms triggered by IL10, TGFB1, and IFNG at the maternal-fetal interface in the presence of T. gondii, contributing to recognizing the importance of these effector mechanisms involved in the vertical transmission of this parasite.

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Section: Discussionsupporting

confidence: 79%

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

Barbosa

Lopes-Maria

Gomes

et al. 2015

Biology of Reproduction

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“…It has been shown that activated caspase 8 and caspase 3 expressions are significantly upregulated in the T . gondii ‐infected trophoblasts . Therefore, in the T .…”

Section: Discussionmentioning

confidence: 99%

“…28,29 It has been shown that activated caspase 8 and caspase 3 expressions are significantly upregulated in the T. gondiiinfected trophoblasts. 30 Therefore, in the T. gondii-induced apoptosis of trophoblasts, Fas ligand-caspase pathway is considered as a major pathway. In vitro TNF-alpha expression in macrophage cell lines has been shown to play a major role in host resistance against toxoplasmosis.…”

Section: Discussionmentioning

confidence: 99%

Increased expressions of ADAMTS‐13 and apoptosis contribute to neuropathology during Toxoplasma gondii encephalitis in mice

Dinçel

Atmaca

2015

Neuropathology

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Toxoplasma gondii (T. gondii) is a protozoan parasite with the potential of causing severe encephalitis among immunocompromised humans and animals. Our previous study showed that T. gondii induces high nitric oxide (NO) production, high glial activation (GFAP) and neurofilament expressions, leading to severe neurodegeneration in toxoplasma encephalitis (TE) in the central nervous system (CNS). The aim of this experimental study was to investigate ADAMTS-13 expression and apoptosis in CNS and to identify whether they have any correlation with toxoplasmosis neuropathology and neurodegeneration. Mice were infected with ME49 strain T. gondii and the levels of ADAMTS-13, caspase 3, caspase 8, caspase 9, TNFR1 and Bcl-xL expressions were examined in brain tissues by immunohistochemistry, during the development and establishment of chronic infections at 10, 30 and 60 days post-infection. Results of the study revealed that the levels of ADAMTS-13 (P < 0.005), caspase 3 (P < 0.05), caspase 8 (P < 0.05), caspase 9 (P < 0.005) and TNFR1 (P < 0.05) expressions in the brain markedly increased while Bcl-xL expression decreased (P < 0.005). The most prominent finding from our study was that 10, 30 and 60 days post-infection ADAMTS-13 increased significantly and this may play an important role in the regulation and protection of the blood-brain barrier integrity and CNS microenvironment in TE. These results also suggest that T. gondii-mediated apoptosis might play a pivotal role and a different type of role in the mechanism of neurodegeneration and neuropathology in the process of TE. Furthermore, expression of ADAMTS-13 might give an idea of the progress and is critical for diagnosis of this disease. To the best of the authors' knowledge, this is the first report on ADAMTS-13 expression in the CNS of T. gondii-infected mice.

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“…Although infection of T. gondii is frequently asymptomatic and self-limiting in nonpregnant individuals, infection in pregnant individuals causes miscarriage, spontaneous abortion, and fetal teratogenesis especially in the early stage of pregnancy. 2 The typical clinical alteration of fetal teratogenesis caused by toxoplasmosis includes chorioretinitis 3 and microcephalia. 4 Previous reports have documented that fetal teratogenesis may be mainly due to immunopathological effects triggered by T. gondii antigens rather than the proliferation of itself at maternal-fetal interface.…”

Section: Introductionmentioning

confidence: 99%

Excreted‐secreted antigens of Toxoplasma gondii inhibit Foxp3 via IL‐2Rγ/JAK3/Stats pathway

Chen

Huang

Zhu

et al. 2018

J of Cellular Biochemistry

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Toxoplasma gondii excreted-secreted antigens (ESA) could lead to the fetal abortion especially in the early stage of pregnancy. Deficit in regulatory T cells is a critical event in the fetal abortion. Transcription factor forkhead box p3 (Foxp3) mediates differentiation and functional roles on regulatory T cells. Previously, we revealed that ESA inhibited Foxp3 through the suppression of transforming growth factor-β type II receptor, phosphorylation of Smad2, Smad3, and Smad4. Knockdown of Smad2 collaborated with ESA to further inhibit Foxp3. The decrease in Foxp3 caused by ESA reversed via forced expression of Smad2, Smad3, and Smad4, respectively. In this study, we investigate whether other signaling pathways are implicated in ESA-induced Foxp3 downregulation. EL4 cells were cultured and stimulated with ESA. Interleukin-2 receptor γ (IL-2Rγ) chain, Janus kinase 3 (JAK3), signal transducer and activator of transcription 5 (Stat5), Stat3, phosphorylation of Stat5 and Stat3 were assayed by Western blot analysis. Phosphorylation of Stat5 and Stat3 was further measured by cellular immunofluorescence. The expression plasmid of pcDNA3.1-Stat3 and pcDNA3.1-Stat5b was constructed, respectively. The concentration of interleukin-2 (IL-2) in the culture supernatants was detected by enzyme-linked immunosorbent assay. ESA inhibited the level of JAK3, phosphorylation of Stat5 and Stat3, and Foxp3 in EL4 cells. The suppressive effects of ESA on Foxp3 were attenuated by forced expression of Stat5 and Stat3. In addition, ESA suppressed IL-2Rγ in EL4 cells, while IL-2Rγ agonist could markedly reverse the diminished Foxp3 caused by ESA. Furthermore, ESA directly influenced the expression of IL-2Rγ, rather than the availability of IL-2 indirectly. ESA suppressed the level of Foxp3 via inhibiting IL-2Rγ/JAK3/Stats signaling pathway in EL4 cells.

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Interferon gamma is involved in apoptosis of trophoblast cells at the maternal–fetal interface following Toxoplasma gondii infection

Cited by 33 publications

References 34 publications

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

Increased expressions of ADAMTS‐13 and apoptosis contribute to neuropathology during Toxoplasma gondii encephalitis in mice

Excreted‐secreted antigens of Toxoplasma gondii inhibit Foxp3 via IL‐2Rγ/JAK3/Stats pathway

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