Simultaneous Stimulation with TGF-β1 and TNF-α Induces Epithelial Mesenchymal Transition in Bronchial Epithelial Cells

Kamitani, Satoshi; Yamauchi, Yasuhiro; Kawasaki, Shin; Takami, Kiyoshi; Takizawa, Hajime; Nagase, Takahide; Kohyama, Tadashi

doi:10.1159/000318854

Cited by 67 publications

(59 citation statements)

References 75 publications

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“…S2A). Because TNFα and TGFβ in combination will induce the EMT in breast cells (42,51,52), we asked if EMT-inducing conditions up-regulate AID expression in mammary epithelial cells. AID (AICDA) mRNA levels, measured by quantitative real-time PCR (real-time qPCR), significantly increased in ZR75.1 (Fig.…”

Section: Mcf10a and Zr751 Cells As Models For The Emt In Normal Andmentioning

confidence: 99%

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

Muñoz¹,

Lee²,

Takayama³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced cytidine deaminase (AID), which functions in antibody diversification, is also expressed in a variety of germ and somatic cells. Evidence that AID promotes DNA demethylation in epigenetic reprogramming phenomena, and that it is induced by inflammatory signals, led us to investigate its role in the epithelialmesenchymal transition (EMT), a critical process in normal morphogenesis and tumor metastasis. We find that expression of AID is induced by inflammatory signals that induce the EMT in nontransformed mammary epithelial cells and in ZR75.1 breast cancer cells. shRNA-mediated knockdown of AID blocks induction of the EMT and prevents cells from acquiring invasive properties. Knockdown of AID suppresses expression of several key EMT transcriptional regulators and is associated with increased methylation of CpG islands proximal to the promoters of these genes; furthermore, the DNA demethylating agent 5 aza-2'deoxycytidine (5-AzadC) antagonizes the effects of AID knockdown on the expression of EMT factors. We conclude that AID is necessary for the EMT in this breast cancer cell model and in nontransformed mammary epithelial cells. Our results suggest that AID may act near the apex of a hierarchy of regulatory steps that drive the EMT, and are consistent with this effect being mediated by cytosine demethylation. This evidence links our findings to other reports of a role for AID in epigenetic reprogramming and control of gene expression.A ctivation-induced cytidine deaminase (AID) belongs to the AID/apolipoprotein B mRNA editing complex catalytic polypeptide (APOBEC) family of cytidine deaminases and is highly expressed in germinal center B lymphocytes, where it is necessary for somatic hypermutation and class switch recombination of the Ig genes (1-3). However, AID is also expressed at much lower levels during B-cell development, where it mediates B-cell tolerance by an as yet undefined mechanism (4, 5). In addition, AID is present at low levels in pluripotent cells such as oocytes, embryonic germ cells, embryonic stem cells (6), and spermatocytes (7), where it may have a function beyond antibody gene diversification (8-10). AID expression is induced by inflammatory paracrine signals such as interleukin-4 (IL-4), tumor necrosis factor alpha (TNFα), and transforming growth factor beta (TGFβ) (11-13), and it has been detected in multiple epithelial tissues in association with chronic inflammatory conditions that promote tumorigenesis (14-18). AID is also expressed in experimentally transformed human mammary epithelial cells (19), and in several cancer cell lines including breast cancer (20, 21). All of this suggests that AID may function in a variety of somatic and germ cell types.AID has been proposed to participate in the demethylation of methylcytosine in DNA (6,(8)(9)(10). Cytosine methylation is a covalent modification of DNA that is present extensively in the vertebrates, predominantly at CpG dinucleotides, where it has a key role in epigenetic mechanisms that suppress transcription initiation...

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Section: Mcf10a and Zr751 Cells As Models For The Emt In Normal Andmentioning

confidence: 99%

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

Muñoz¹,

Lee²,

Takayama³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…the combination of TNF-a and TGFb, IL-1b, or a cytomix (19)(20)(21). Here, we show that a phenotypic shift can occur in alveolar cells and BECs through TNF-a only.…”

Section: Discussionmentioning

confidence: 64%

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

Eurlings

Reynaert

Wetering

et al. 2017

Am J Respir Cell Mol Biol

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Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) is characterized by airway wall thickening and/or emphysema. Although the bronchial and alveolar compartments are functionally independent entities, we recently showed comparable alterations in matrix composition comprised of decreased elastin content and increased collagen and hyaluronan contents of alveolar and small airway walls. Out of several animal models tested, surfactant protein C (SPC)-TNF-a mice showed remodeling in alveolar and airway walls similar to what we observed in patients with COPD. Epithelial cells are able to undergo a phenotypic shift, gaining mesenchymal properties, a process in which c-Jun N-terminal kinase (JNK) signaling is involved. Therefore, we hypothesized that TNF-a induces JNK-dependent epithelial plasticity, which contributes to lung matrix remodeling. To this end, the ability of TNF-a to induce a phenotypic shift was assessed in A549, BEAS2B, and primary bronchial epithelial cells, and phenotypic markers were studied in SPC-TNF-a mice. Phenotypic markers of mesenchymal cells were elevated both in vitro and in vivo, as shown by the expression of vimentin, plasminogen activator inhibitor-1, collagen, and matrix metalloproteinases. Concurrently, the expression of the epithelial markers, E-cadherin and keratin 7 and 18, was attenuated. A pharmacological inhibitor of JNK attenuated this phenotypic shift in vitro, demonstrating involvement of JNK signaling in this process. Interestingly, activation of JNK signaling was also clearly present in lungs of SPC-TNF-a mice and patients with COPD. Together, these data show a role for TNF-a in the induction of a phenotypic shift in vitro, resulting in increased collagen production and the expression of elastin-degrading matrix metalloproteinases, and provide evidence for involvement of the TNF-a-JNK axis in extracellular matrix remodeling.

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“…Initial evidence came from in vitro studies where airway and alveolar epithelial cells could be induced to undergo EMT by transforming growth factor (TGF) family proteins [Willis et al, 2005;Molloy et al, 2008;Kamitani et al, 2011]. Such evidence demonstrated that airway epithelial cells retained the potential to undergo EMT.…”

Section: Evidence For Emt In Copdmentioning

confidence: 99%

“…Cell culture models have shown that both the TGF-β-dependent Smad pathway, as well as the TGF-β-independent Wnt/β-catenin pathway, can be involved in the induction of EMT in COPD in response to different stimuli [Camara and Jarai, 2010;Kamitani et al, 2011;Zou et al, 2013]. The actions of the Smad pathway are, in particular, known to be enhanced in the presence of pro-inflammatory cytokines, such as tumor necrosis factor-α, and a culture environment that mimics a proinflammatory situation further exacerbates EMT progression [Camara and Jarai, 2010], suggesting that the chronic bronchitis aspect commonly observed in COPD may play an important role in the development and progression of fibrosis via the promotion of EMT.…”

Section: Drivers and Mechanisms Of Emt In Airway Epitheliummentioning

confidence: 99%

The Role of Epithelial-Mesenchymal Transition in Chronic Obstructive Pulmonary Disease

Courtney¹,

Spafford²

2017

Cells Tissues Organs

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Chronic obstructive pulmonary disease (COPD) is a major cause of mortality worldwide, and there is currently no treatment that can halt the progression of the disease. Over the last decade there has been increasing interest in the idea that epithelial-mesenchymal transition (EMT) may be active in COPD. Here we review the evidence for EMT in COPD as well as the current progress being made on understanding the drivers and mechanisms involved. Finally, we discuss the potential benefits that understanding EMT may bring to the field of chronic respiratory disease.

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Simultaneous Stimulation with TGF-β1 and TNF-α Induces Epithelial Mesenchymal Transition in Bronchial Epithelial Cells

Cited by 67 publications

References 75 publications

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

Activation-induced cytidine deaminase (AID) is necessary for the epithelial–mesenchymal transition in mammary epithelial cells

Involvement of c-Jun N-Terminal Kinase in TNF-α–Driven Remodeling

The Role of Epithelial-Mesenchymal Transition in Chronic Obstructive Pulmonary Disease

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