Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells

Miller, Michelle L.; Mashayekhi, Mona; Chen, Luqiu; Zhou, Ping; Liu, Xindong; Michelotti, Monica; Gunn, Nicole Tramontini; Powers, Sarah E.; Zhu, Xiaoping; Evaristo, César; Alegre, Maria Luisa; Molinero, Luciana

doi:10.1073/pnas.1315398111

Cited by 31 publications

(35 citation statements)

References 47 publications

(52 reference statements)

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“…Miller ML et al has shown that NF-κB pathway is responsible for the transcription of the IL-7R gene in T cells [15]. Additionally, Wang H et al indicates that Notch1 pathway is associated with the expression of IL-7R in T cells and T-lymphoblastic leukemia [16].…”

Section: Resultsmentioning

confidence: 99%

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Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Kong

Zhou

et al. 2016

J Exp Clin Cancer Res

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BackgroundInterleukin-7 receptor (IL-7R) is involved in the abnormal function of solid tumors, but the role and regulatory mechanisms of IL-7R in HBV-related hepatocellular carcinoma (HCC) are still unclear.MethodsGene and protein expression levels of IL-7R were examined in hepatoma cells transfected with hepatitis B virus (HBV) plasmids and in hepatoma cells transfected with the multifunctional nonstructural protein X (HBX). The expression of HBX and IL-7R was measured by immunohistochemical analysis in HBV-related HCC tissues. The role of NF-κB and Notch1 pathways in HBX-mediated expression of IL-7R in hepatoma cells was examined. Activation of IL-7R downstream of intracellular signaling proteins AKT, JNK, STAT5, and the associated molecules CyclinD1 and matrix metalloproteinase-9 (MMP)-9, was assessed in HBX-positive cells with or without treatment with IL-7R short hairpin RNA (shRNA). Additionally, the role of IL-7R in HBX-mediated proliferation and migration of hepatoma cells was investigated.ResultsThe expression of IL-7R was increased in hepatoma cells transfected with HBV plasmids; HBX was responsible for the HBV-mediated upregulation of IL-7R. Compared to adjacent tissues, the expression of HBX and IL-7R was increased in HBV-related HCC tissues. Additionally, the relative expression levels of HBX were associated with IL-7R in HBV-related HCC tissues. The activation of NF-κB pathways and expression of Notch1 were increased in hepatoma cells transfected with HBX, and inhibition of NF-κB and Notch1 pathways significantly decreased HBX-mediated expression of IL-7R. The activation of AKT and JNK and the expression of CyclinD1 and MMP-9 were increased in HBX-positive cells. When cells were treated with IL-7R shRNA, the activation of AKT and JNK, as well as the expression of CyclinD1 and MMP-9, were significantly inhibited. Additionally, IL-7R was responsible for HBX-induced proliferation and migration ability of hepatoma cells.ConclusionsOur data demonstrate that HBX can upregulate IL-7R via NF-κB and Notch1 pathways to facilitate the activation of intracellular pathways and expression of associated molecules, and contribute to proliferation and migration of hepatoma cells.

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Section: Resultsmentioning

confidence: 99%

“…Miller ML et al indicated that NF-κB pathways mediate the transcription of IL-7 receptor, thereby controlling the responsiveness of quiescent naïve T cells to IL-7 [15]. Tian B et al has shown that the tumor necrosis factor (TNF)-mediated expression of IL-7R is also dependent on NF-κB pathways in HeLa cells [25].…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Kong

Zhou

et al. 2016

J Exp Clin Cancer Res

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“…NF- κ B regulates inflammation, 6,7 and we recently demonstrated the biological relevance of NF- κ B in ovarian cancer. Coordinated expression of NF- κ B transcription factors and target genes were associated with poor overall survival and aggressive tumor behavior.…”

Section: Introductionmentioning

confidence: 95%

A dual role for Caspase8 and NF-κB interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival

Hernandez

Kim

Noonan

et al. 2015

Cell Death Discovery

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Ovarian cancer is a deadly disease characterized by primary and acquired resistance to chemotherapy. We previously associated NF-κB signaling with poor survival in ovarian cancer, and functionally demonstrated this pathway as mediating proliferation, invasion and metastasis. We aimed to identify cooperating pathways in NF-κB-dependent ovarian cancer cells, using genome-wide RNA interference as a loss-of-function screen for key regulators of cell survival with IKKβ inhibition. Functional genomic screen for interactions with NF-κB in ovarian cancer showed that cells depleted of Caspase8 died better with IKKβ inhibition. Overall, low Caspase8 was associated with shorter overall survival in three independent gene expression data sets of ovarian cancers. Conversely, Caspase8 expression was markedly highest in ovarian cancer subtypes characterized by strong T-cell infiltration and better overall prognosis, suggesting that Caspase8 expression increased chemotherapy-induced cell death. We investigated the effects of Caspase8 depletion on apoptosis and necroptosis of TNFα-stimulated ovarian cancer cell lines. Inhibition of NF-κB in ovarian cancer cells switched the effects of TNFα signaling from proliferation to death. Although Caspase8-high cancer cells died by apoptosis, Caspase8 depletion downregulated NF-κB signaling, stabilized RIPK1 and promoted necroptotic cell death. Blockage of NF-κB signaling and depletion of cIAP with SMAC-mimetic further rendered these cells susceptible to killing by necroptosis. These findings have implications for anticancer strategies to improve outcome for women with low Caspase8-expressing ovarian cancer.

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“…Stimulation with tumor necrosis factor (TNF), which is known to act through NF-kB, resulted in a slight increase in NF-kB phosphorylation across the naive CD4 + T cell population regardless of CD31 expression (S Fig 5B). Interestingly, basal NF-kB phosphorylation has been shown to play an important role in determining naïve T cell survival in rodents [48,49], prompting us to investigate this pathway further.…”

Section: Single Cell Proteomic Analysis Of Cd4 + Naïve T Cells Revealmentioning

confidence: 99%

Cell generation dynamics underlying naïve T cell homeostasis in adult humans

Mold

Réu

Olin

et al. 2019

Preprint

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Thymic involution and proliferation of naive T cells both contribute to shaping the naive T cell repertoire as humans age, but a clear understanding of the roles of each throughout a human lifespan has been difficult to determine. By measuring nuclear bomb test-derived 14 C in genomic DNA we determined the turnover rates of CD4 + and CD8 + naïve T cell populations and defined their dynamics in healthy individuals ranging from 20-65 years of age. We demonstrate that naïve T cell generation decreases with age, and that this could be explained by a combination of declining cell loss, peripheral division and thymic production during adulthood. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of naïve T cell turnover using mass cytometry to profile candidate signaling pathways involved in T cell activation and proliferation in CD4 + naive T cells relative to CD31 expression, a marker of thymic proximity. We show that basal NF-kB phosphorylation inversely correlated with CD31 expression and thus is decreased in peripherally expanded naive T cell clones. Functionally we found that NF-kB signaling was essential for naive T cell proliferation to the homeostatic growth factor IL-7, and reduced NF-kB phosphorylation in CD4 + CD31naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naïve T cell turnover as a putative regulator of naïve T cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T cell clones that accumulate with age.

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Basal NF-κB controls IL-7 responsiveness of quiescent naïve T cells

Cited by 31 publications

References 47 publications

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

Hepatitis B virus X protein promotes interleukin-7 receptor expression via NF-κB and Notch1 pathway to facilitate proliferation and migration of hepatitis B virus-related hepatoma cells

A dual role for Caspase8 and NF-κB interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival

Cell generation dynamics underlying naïve T cell homeostasis in adult humans

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