Inflammation and Lung Cancer: The Role of Epithelial–Mesenchymal Transition

Walser, Tonya C.; Park, Stacy J.; Yanagawa, Jane; Dubinett, Steven M.

doi:10.1007/978-1-4939-2724-1_2

Cited by 4 publications

(8 citation statements)

References 254 publications

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“…However, in some circumstances, elevated IL-10 levels can exhaust antiviral T cells and induce immunosuppression, which enables viral persistence [27]. In addition, proinflammatory cytokines are important factors in chronic inflammatory responses that promote the epithelial-mesenchymal transition (EMT), suggesting that persistent TGEV infection may promote EMT in vivo [28,29]. TGF-β also functions in immune suppression and plays an important role in viral persistence [30], and TGF-β signaling has been shown to promote IL-10 gene transcription [31].…”

Section: Discussionmentioning

confidence: 99%

Impact of TGEV infection on the pig small intestine

Yang

Wang

et al. 2018

Virol J

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BackgroundPig diarrhea causes high mortality and large economic losses in the swine industry. Transmissible gastroenteritis virus (TGEV) causes pig diarrhea, with 100% mortality in piglets less than 2 weeks old. No investigation has yet been made of the small intestine of piglets that survived infection by TGEV.MethodsIn this study, we evaluated the impact of TGEV infection on the small intestine of recovered pigs.ResultsHistological analyses showed that TGEV infection led to villi atrophy, and reduced villous height and crypt depth. The number of SIgA positive cells, CD3+T cells, and dendritic cells (DCs) in jejunum decreased after TGEV infection in vivo. In contrast, microfold cell (M cell) numbers and cell proliferation increased in infected pigs. TGEV infection also significantly enhanced the mRNA expression levels of cytokine IL-1β, IL-6, TNF-α, IL-10, and TGF-β. Additionally, lower gene copy numbers of Lactobacillus, and higher numbers of Enterobacteriaceae, were detected in mucosal scraping samples from TGEV-infected pigs.ConclusionsTGEV infection damages the small intestine, impairs immune functions, and increases pathogenic bacterial loading, all of which may facilitate secondary infections by other pathogens. These findings help quantify the impact of TGEV infection and clarify the pathogenic mechanisms underlying its effects in pigs.

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Section: Discussionmentioning

confidence: 99%

Impact of TGEV infection on the pig small intestine

Yang

Wang

et al. 2018

Virol J

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“…It is tightly controlled by GSK3␤ phosphorylation. The phosphorylation of GSK3␤ facilitates GSK3␤ ubiquitination and subsequent degradation, which promotes the stability and nuclear translocation of ␤-catenin (26). Finally, TGEV infection also activates the transcription factor twist, which acts as a transcriptional repressor of E-cadherin (27).…”

Section: Discussionmentioning

confidence: 99%

“…TGEV infection markedly increases the expression levels of IL-1␤, IL-6, IL-8, TNF-␣, and TGF-␤, which are important factors in chronic inflammation (26). Inflammatory conditions induced by pathogen infections promote EMT, because inflammation leads to the sustained activation of the NF-B and mitogen-activated protein kinase (MAPK) modules, which control the expression of mesenchymal markers (27).…”

Section: Discussionmentioning

confidence: 99%

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Persistent Transmissible Gastroenteritis Virus Infection Enhances Enterotoxigenic Escherichia coli K88 Adhesion by Promoting Epithelial-Mesenchymal Transition in Intestinal Epithelial Cells

Dai

et al. 2017

J Virol

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Transmissible gastroenteritis virus (TGEV) is a coronavirus characterized by diarrhea and high morbidity rates, and the mortality rate is 100% in piglets less than 2 weeks old. Pigs infected with TGEV often suffer secondary infection by other pathogens, which aggravates the severity of diarrhea, but the mechanisms remain unknown. Here, we hypothesized that persistent TGEV infection stimulates the epithelial-mesenchymal transition (EMT), and thus enterotoxigenic (ETEC) can more easily adhere to generating cells. Intestinal epithelial cells are the primary targets of TGEV and ETEC infections. We found that TGEV can persistently infect porcine intestinal columnar epithelial cells (IPEC-J2) and cause EMT, consistent with multiple changes in key cell characteristics. Infected cells display fibroblast-like shapes; exhibit increases in levels of mesenchymal markers with a corresponding loss of epithelial markers; have enhanced expression levels of interleukin-1β (IL-1β), IL-6, IL-8, transforming growth factor β (TGF-β), and tumor necrosis factor alpha (TNF-α) mRNAs; and demonstrate increases in migratory and invasive behaviors. Additional experiments showed that the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) signaling pathways via TGF-β is critical for the TGEV-mediated EMT process. Cellular uptake is also modified in cells that have undergone EMT. TGEV-infected cells have higher levels of integrin α5 and fibronectin and exhibit enhanced ETEC K88 adhesion. Reversal of EMT reduces ETEC K88 adhesion and inhibits the expression of integrin α5 and fibronectin. Overall, these results suggest that TGEV infection induces EMT in IPEC-J2 cells, increasing the adhesion of ETEC K88 in the intestine and facilitating dual infection. Transmissible gastroenteritis virus (TGEV) causes pig diarrhea and is often followed by secondary infection by other pathogens. In this study, we showed that persistent TGEV infection induces an EMT in porcine intestinal columnar epithelial cells (IPEC-J2) and enhances the adhesion of the secondary pathogen ETEC K88. Additional experiments suggest that integrin α5 and fibronectin play an important role in TGEV-enhanced ETEC K88 adhesion. Reversal of EMT reduces the expression of integrin α5 and fibronectin and also reduces ETEC K88 adhesion. We conclude that TGEV infection triggers EMT and facilitates dual infection. Our results provide new insights into secondary infection and suggest that targeted anti-EMT therapy may have implications for the prevention and treatment of secondary infection.

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“…Activated fibroblasts are the principle mediators of tissue remodeling, and one of the key sources of fibroblast accumulation is thought to be epithelial–mesenchymal transition (EMT) . In EMT, epithelial cells transform to activated fibroblasts, and transforming growth factor (TGF)‐β1 is a recognized master switch for this process . EMT is demonstrated by downregulation of epithelial markers such as E‐cadherin and increased expression of mesenchymal markers including fibronectin, matrix metalloproteinase (MMP)‐9, and procollagen from epithelial cells .…”

Section: Introductionmentioning

confidence: 99%