IFN-γ Mediates Enhancement of HIV Replication in Astrocytes by Inducing an Antagonist of the β-Catenin Pathway (DKK1) in a STAT 3-Dependent Manner

Li, Wei; Henderson, Lee A.; Major, Eugene O.; Al‐Harthi, Lena

doi:10.4049/jimmunol.1100099

Cited by 80 publications

(96 citation statements)

References 42 publications

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“…3 and 4). This is consistent with the results of our previous study in human astroglioma cells, in which IFNγ regulates the β-catenin pathway in a STAT3-dependent manner, in which STAT1 it is not necessarily involved (21).…”

Section: A B C Dsupporting

confidence: 93%

“…To further identify the key signaling components for IFNγ to induce apoptosis in HepG2 cells that express excess β-catenin, we used inhibitors for STAT1, STAT3 and caspases. In a previous study, we demonstrated that STAT1 and STAT3 were induced by IFNγ in human astroglioma cells, in which STAT3 played a key role in the regulation of the β-catenin pathway (21). In the present study, we confirmed the STAT1 and STAT3 activation induced by IFNγ, and the effects of STAT1 inhibitor, FLUD, and STAT3 inhibitor, S3I, in HepG2 cells with high levels of (Fig.…”

Section: Roles Of Stats and Caspases In Ifnγ-induced Apoptosis Insupporting

confidence: 85%

“…In addition, we aimed to identify key modulators in this regulation. Studies concerning the regulation of the β-catenin pathway by IFNγ have been published (21,25). We have shown that the β-catenin pathway regulates IFNγ signaling.…”

Section: Discussionmentioning

confidence: 92%

“…Previously, we studied the regulation of IFNγ and the β-catenin/Wnt signaling pathway in human astrocytes (21). In the present study, we intended to investigate the effect of upregulated β-catenin on IFNγ-induced apoptosis in human liver carcinoma cells, the molecular mechanisms by which this occurs.…”

Section: Introductionmentioning

confidence: 99%

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High levels of β-catenin promote IFNγ-induced apoptosis in hepatocellular carcinoma cells

Tong

Huang

et al. 2012

Oncology Letters

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Abstract. β-catenin is a multifunctional protein that is involved in cellular structure and the Wnt/β-catenin signaling pathway. Wnt/β-catenin signaling is believed to be an inducer of cell proliferation in different tumors. However, in certain physiological contexts β-catenin also promotes apoptosis. High levels of β-catenin are found in a number of cancer cell types. Recent studies have shown that β-catenin may be correlated with carcinogenesis. Its effects and interaction with interferon (IFN)γ signaling in hepatocellular carcinoma (HCC) cells remains unknown. In the present study, high levels of β-catenin did not induce antiproliferative effects or apoptosis and did not lead to changes in the levels of caspases or activated STATs. However, high levels of β-catenin did cause positive p53 accumulation and Bcl-XL downregulation in HepG2 cells, a HCC cell line. When treated with IFNγ, apoptosis was induced more rapidly compared with cells with low β-catenin levels (P<0.05), whereas caspases 3, 8 and 9 were markedly activated. The caspase inhibitor Z-VAD-FMK and the STAT3 inhibitor blocked this IFNγ-induced apoptosis. Therefore, we report that high levels of β-catenin promote IFNγ-induced apoptosis in HCC in a caspase-and STAT3-dependent manner, and facilitate the activation of executor caspases, possibly via regulation of p53 and Bcl-XL levels. These findings may provide foundations for the development of new IFN-based therapies against liver cancer.

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Section: A B C Dsupporting

confidence: 93%

Section: Roles Of Stats and Caspases In Ifnγ-induced Apoptosis Insupporting

confidence: 85%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

High levels of β-catenin promote IFNγ-induced apoptosis in hepatocellular carcinoma cells

Tong

Huang

et al. 2012

Oncology Letters

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“…Flow cytometry was performed as previously described (27). FITC-conjugated mouse anti-human activated STAT1 antibody was purchased from Cell Signaling, USA.…”

Section: Methodsmentioning

confidence: 99%

Type III interferon induces apoptosis in human lung cancer cells

Huang

Liu

et al. 2012

Oncology Reports

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Abstract. The apoptotic effects of interferon lambdas (IFNλs) have been described in several types of cancers. However, their effects on human lung cancer cells and the mechanisms are elusive. In addition, the interaction between IFNλs and other interferons remains unclear. The interplay between IFNα and IFNλ has been reported. However, although IFNγ is a well-known regulatory interferon, the mechanisms through which it regulates IFNλs in lung cancer cells are unknown. These issues are critical for the application of IFNλs in lung cancer therapy. In this study, we used A549, a cell line derived from a human lung carcinoma, to characterize the antiproliferative and apoptotic effects of IFNλs on lung cancer, and the interplay between IFNγ and IFNλ. Because overexpression of full-length ectopic IFNλR1 led to cell death, we generated A549 cells stably expressing a chimeric receptor (10R1/ λR1), which is composed of the extracellular domain of IL-10 receptor (IL10R1) fused in tandem to the transmembrane and intracellular domains of the IFNλ receptor (IFNλR1). By comparing with A549 cells stably expressing its cognate vector, we demonstrated that IL-10 stimulation triggered the intracellular IFNλ signaling via 10R1/λR1 receptor. By using A549 cells expressing 10R1/λR1, we report that the IFNλR1 chain of IFNλ receptor possesses an intrinsic ability to trigger apoptosis in human lung cancer cells. Although it did not suppress cell proliferation, IFNλ signaling via 10R1/ λR1 receptor induced cell cycle arrest, externalization of phosphatidylserine, DNA fragmentation, activation of caspase-3, caspase-8 and caspase-9. However, the caspase inhibitor Z-VAD-FMK did not prevent apoptosis. In addition, the extent of induced apoptosis correlate with the expression levels of the IFNλ receptor and the levels of STAT1 activation. Lastly, we demonstrated that IFNγ sensitized A549 cells to IFNλ-induced apoptosis, via upregulation of IFNλR1. These data indicate the potential of IFNλ, alone or in combination with IFNγ, in the treatment of human lung carcinoma.

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Dynamic interaction between astrocytes and infiltrating PBMCs in context of neuroAIDS

Richards

Narasipura

Kim

et al. 2014

Glia

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HIV-mediated neuropathogenesis is a multifaceted process involving several players, including resident brain cells (neurons, astrocytes, and microglia) and infiltrating cells (peripheral blood mononuclear cells (PBMCs)). We evaluated the dynamic interaction between astrocytes and infiltrating PBMCs as it impacts HIV in the CNS. We demonstrate that human primary-derived astrocytes (PDAs) predominantly secrete Wnt 1, 2b, 3, 5b, and 10b. Wnts are small secreted glycoproteins that initiate either β-catenin-dependent or independent signal transduction. The Wnt pathway plays a vital role in the regulation of CNS activities including neurogenesis, neurotransmitter release, synaptic plasticity, and memory consolidation. We show that HIV infection of PDAs altered astrocyte Wnt profile by elevating Wnts 2b and 10b. Astrocyte conditioned media (ACM) inhibited HIV replication in PBMCs by 50%. Removal of Wnts from ACM abrogated its ability to suppress HIV replication in PBMCs. Inversely, PBMCs supernatant activated PDAs, as demonstrated by a 10-fold increase in HLA-DR and a 5-fold increase in IFNγ expression, and enhanced astrocyte susceptibility to HIV by 2-fold, which was mediated by IFNγ in a Stat-3-dependent manner. Collectively, these data demonstrate a dynamic interaction between astrocytes and PBMCs, whereby astrocyte-secreted Wnts exert an anti-HIV effect on infected PBMCs and PBMCs, in turn, secrete IFNγ that enhance astrocyte susceptibility to productive HIV infection and mediate their activation.

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IFN-γ Mediates Enhancement of HIV Replication in Astrocytes by Inducing an Antagonist of the β-Catenin Pathway (DKK1) in a STAT 3-Dependent Manner

Cited by 80 publications

References 42 publications

High levels of β-catenin promote IFNγ-induced apoptosis in hepatocellular carcinoma cells

High levels of β-catenin promote IFNγ-induced apoptosis in hepatocellular carcinoma cells

Type III interferon induces apoptosis in human lung cancer cells

Dynamic interaction between astrocytes and infiltrating PBMCs in context of neuroAIDS

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