In vitro effects of interleukin (IL)-1 beta inhibition on the epithelial-to-mesenchymal transition (EMT) of renal tubular and hepatic stellate cells

Masola, Valentina; Carraro, Amedeo; Granata, Simona; Signorini, Lorenzo; Bellin, Gloria; Violi, Paola; Lupo, Antonio; Tedeschi, Umberto; Onisto, Maurizio; Gambaro, Giovanni; Zaza, Gianluigi

doi:10.1186/s12967-019-1770-1

Cited by 65 publications

(44 citation statements)

References 50 publications

(50 reference statements)

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“…Particularly noteworthy, the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) revealed that IL-1β inhibition with the neutralizing antibody canakinumab decreases both the incidence and mortality of lung cancer in patients with atherosclerosis co-morbidities 13 . Although our previous studies and those from others demonstrated that acute IL-1β exposure induces the expression of genes associated with transformation, invasion, and metastasis in multiple malignancies, including lung cancer, the impact of chronic IL-1β exposure, which may be more physiologically relevant, has not yet been defined [14][15][16][17][18][19][20] .…”

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confidence: 86%

Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer

Ong

Tran

et al. 2020

Sci Rep

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Chronic inflammation facilitates tumor progression. We discovered that a subset of non-small cell lung cancer cells underwent a gradually progressing epithelial-to-mesenchymal (EMT) phenotype following a 21-day exposure to IL-1β, an abundant proinflammatory cytokine in the at-risk for lung cancer pulmonary and the lung tumor microenvironments. Pathway analysis of the gene expression profile and in vitro functional studies revealed that the EMT and EMT-associated phenotypes, including enhanced cell invasion, PD-L1 upregulation, and chemoresistance, were sustained in the absence of continuous IL-1β exposure. We referred to this phenomenon as EMT memory. Utilizing a doxycyclinecontrolled SLUG expression system, we found that high expression of the transcription factor SLUG was indispensable for the establishment of EMT memory. High SLUG expression in tumors of lung cancer patients was associated with poor survival. Chemical or genetic inhibition of SLUG upregulation prevented EMT following the acute IL-1β exposure but did not reverse EMT memory. Chromatin immunoprecipitation and methylation-specific PCR further revealed a SLUG-mediated temporal regulation of epigenetic modifications, including accumulation of H3K27, H3K9, and DNA methylation, in the CDH1 (E-cadherin) promoter following the chronic IL-1β exposure. Chemical inhibition of DNA methylation not only restored E-cadherin expression in EMT memory, but also primed cells for chemotherapy-induced apoptosis. Dysregulated inflammation is recognized as one of the hallmarks of cancer and is involved in tumor initiation, progression, and metastasis 1-3. Chronic inflammatory conditions, such as chronic obstructive pulmonary disease or ulcerative colitis, are strongly associated with elevated cancer incidence 4-6. Chronic use of aspirin or other non-steroidal anti-inflammatory drugs reduces mortality of esophageal, colorectal, and lung cancers 7,8. Interleukin-1 beta (IL-1β), a proinflammatory cytokine, correlates with tumor progression in non-small cell lung cancer (NSCLC) patients in multiple studies. Wu et al. found an elevated level of serum IL-1β in NSCLC patients compared to healthy donors. Elevated IL-1β in these patients is associated with poor survival 9 .

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confidence: 86%

Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer

Ong

Tran

et al. 2020

Sci Rep

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“…For instance, KCs can respond to exposure to LPS by binding to TLR4 which leads to production of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-12, IL-18, etc.) and other chemokines [72], most of them being actively involved in HSCs activation (Table 2) [5,[73][74][75]. Other macrophages recruited to the liver in the case of inflammation, are also involved in secretion of pro-and anti-inflammatory cytokines, depending on their type (proinflammatory M1 or immunosuppressive M2, respectively).…”

Section: Inflammatory Signals From Kupffer Cells and Other Inflammatimentioning

confidence: 99%

Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development

Ignat

Dinescu

Costache

2020

Cells

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Inflammation has been known to be an important driver of fibrogenesis in the liver and onset of hepatic fibrosis. It starts off as a process meant to protect the liver from further damage, but it can become the main promoter of liver fibrosis. There are many inflammation-related pathways activated during liver fibrosis that lead to hepatic stellate cells (HSCs) activation and collagen-deposition in the liver. Such events are mostly modulated upstream of HSCs and involve signals from hepatocytes and innate immune cells. One particular event is represented by cell death during liver injury that generates multiple inflammatory signals that further trigger sterile inflammation and enhancement of inflammatory response. The assembly of inflammasome that responds to danger-associated molecular patterns (DAMPs) stimulates the release of pro-inflammatory cytokines and at the same time, initiates programmed cell death called pyroptosis. This review focuses on cellular and molecular mechanisms responsible for initiation and progress of inflammation in the liver.

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“…Western blot using specific monoclonal antibodies of α-SMA and fibronectin confirmed our previous observation and showed the elevation in the steady-state levels of both cell-associated ECM proteins ( Figure 2C ). Because HG upregulates fibronectin ( 27 ), and IL-1 treatment causes a fibrotic-like state in human HK-2 cells in vitro ( 28 ), we tested the possibility that the IL-1α-dependent primary intrinsic inflammation, which stimulates cells to adopt an activated state characterized by enhanced expression of ECM protein production, can be attenuated by IL-1Ra. In support of our hypothesis, when tested in an animal rat model, administration of an IL-1Ra almost completely abrogated tubular atrophy ( 29 ).…”

Section: Resultsmentioning

confidence: 99%

Glucose Induces IL-1α-Dependent Inflammation and Extracellular Matrix Proteins Expression and Deposition in Renal Tubular Epithelial Cells in Diabetic Kidney Disease

et al. 2020

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Diabetes mellitus is linked with metabolic stress that induces cellular damage and can provoke renal inflammation and fibrotic responses that eventually lead to chronic kidney disease. Because the inflammasome, interleukin 1 (IL-1), IL-1α/IL-β, and IL-1R are central elements of kidney inflammation and pharmacological IL-1R antagonist (IL-1Ra) was shown to prevent or even reverse diabetic nephropathy (DN) in animal models, we explored the intrinsic expression of IL-1 molecules in kidney tissue of DN patients as regulators of renal inflammation. We used biopsies taken from DN patients and controls and show a high level of IL-1α expression in renal tubular epithelial cells, whereas both IL-1 agonistic molecules (i.e., IL-1α and IL-1β) were devoid of the glomeruli. Human proximal tubular kidney HK-2 cells exposed to high glucose (HG) gradually increase the expression of IL-1α but not IL-1β and induce the expression and deposition of extracellular matrix (ECM) proteins. We further demonstrate that in vitro ectopic addition of recombinant IL-1α in low glucose concentration leads to a similar effect as in HG, while supplementing excess amounts of IL-1Ra in HG significantly attenuates the ECM protein overexpression and deposition. Accordingly, inhibition of IL-1α cleaving protease calpain, but not caspapse-1, also strongly reduces ECM protein production by HK-2 cells. Collectively, we demonstrate that IL-1α and not IL-1β, released from renal tubular cells is the key inflammatory molecule responsible for the renal inflammation in DN. Our result suggests that the clinical use of IL-1Ra in DN should be promoted over the individual neutralization of IL-1α or IL-1β in order to achieve better blocking of IL-1R signaling.

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In vitro effects of interleukin (IL)-1 beta inhibition on the epithelial-to-mesenchymal transition (EMT) of renal tubular and hepatic stellate cells

Cited by 65 publications

References 50 publications

Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer

Chronic IL-1β-induced inflammation regulates epithelial-to-mesenchymal transition memory phenotypes via epigenetic modifications in non-small cell lung cancer

Cellular Interplay as a Consequence of Inflammatory Signals Leading to Liver Fibrosis Development

Glucose Induces IL-1α-Dependent Inflammation and Extracellular Matrix Proteins Expression and Deposition in Renal Tubular Epithelial Cells in Diabetic Kidney Disease

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