Interleukin 6 and <scp>STAT</scp>3 regulate p63 isoform expression in keratinocytes during regeneration

Nelson, Amanda M.; Katseff, Adiya S.; Ratliff, Tabetha S.; Garza, Luis A.

doi:10.1111/exd.12896

Cited by 13 publications

(13 citation statements)

References 10 publications

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“…IL-6 triggers mammosphere formation and CSC self-renewal in breast cancer cells 20 and has also been demonstrated to increase lung CSC populations 21. Previously, Nelson et al reported that IL-6 promoted the expression of the p63 isomer in keratinocytes during regeneration 22; however, the precise link between IL-6 and ΔNp63α in long-term TS-induced lung CSC-like properties has not yet been described.…”

Section: Introductionmentioning

confidence: 99%

Sulforaphane Inhibits the Acquisition of Tobacco Smoke-Induced Lung Cancer Stem Cell-Like Properties via the IL-6/ΔNp63α/Notch Axis

Xie

Zhu

Jiang³

et al. 2019

Theranostics

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Background: Tobacco smoke (TS) critically contributes to the development of lung cancer; however, the underlying molecular mechanisms remain unclear. The induction of cancer stem cells (CSCs) by TS represents an early event in tumor initiation. The lung cancer-related gene ΔNp63α is highly expressed in epithelial tissues and drives tumor formation and cancer stem cell properties. This study investigated the role of ΔNp63α in the long-term acquisition of TS-induced lung CSC-like properties. Methods: The expression levels of ΔNp63α, lung CSC markers, and interleukin (IL)-6 in lung carcinoma specimens were determined by western blotting and enzyme linked immunosorbent assays. Human bronchial epithelial (HBE) cells were chronically exposed to 2 % cigarette smoke extract for 55 passages, following which colony formation capacity, expression of proteins associated with malignant transformation, lung CSC markers, and tumor incidence were investigated. The effects of ΔNp63α on long-term TS exposure-induced lung CSC-like properties and Notch activation were analyzed using tumorsphere formation ability, immunofluorescence assays, luciferase reporter assays, and western blotting. The roles of IL-6 on chronic TS exposure-induced lung CSC-like properties and ΔNp63α expression were also examined. Moreover, the effects of sulforaphane (SFN) on TS-transformed lung CSC-like properties, IL-6 and ΔNp63α expression, and Notch signaling were investigated in vitro and in vivo . Results: Higher levels of ΔNp63α were observed in the lung cancer tissues of smokers than in those of non-smokers, whereas ΔNp63α was positively correlated with CD133 and Oct4 expression in lung cancer tissues. Data from the in vivo and in vitro experiments demonstrated that long-term TS exposure-transformed HBE (THBE) cells acquired lung CSC-like properties. Furthermore, ΔNp63α transcriptionally activated the Notch signaling pathway to promote the acquisition of CSC-like properties by the THBE cells. TS upregulated IL-6, which increased ΔNp63α expression in THBE sphere-forming cells. Finally, SFN inhibited the TS-induced CSC-like properties of THBE cells via the IL-6/ΔNp63α/Notch axis. Conclusion : Our data suggest that the IL-6/ΔNp63α/Notch axis plays an important role in the long-term TS exposure-induced acquisition of lung CSC-like properties and SFN intervention.

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Section: Introductionmentioning

confidence: 99%

Sulforaphane Inhibits the Acquisition of Tobacco Smoke-Induced Lung Cancer Stem Cell-Like Properties via the IL-6/ΔNp63α/Notch Axis

Xie

Zhu

Jiang³

et al. 2019

Theranostics

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“…We found the cycle-related expression of RIPK-1 and RIPK-3 in mouse and human HF cells: It was found in the anagen HFs and absent in telogen ones ( Morgun et al, 2020 ). As it was described above, hair growth may be promoted via dsRNA/TLR3/IL-6/STAT3 pathway ( Nelson et al, 2015 , 2016a _A; Nelson et al, 2016b _B). Based on Moriwaki data obtained in a mouse model of colitis, as well as in an experiment on bone-marrow-derived dendritic cells, it can be concluded that after LPS-induced stimulation of TLR4, RIPK-3 participates in the activation of the NF-κβ pathway, which leads to interleukin expression and STAT3 phosphorylation ( Moriwaki et al, 2014 ).…”

Section: Discussionmentioning

confidence: 95%

“…Besides, the participation of IL-6/STAT3 pathway in the acquisition of stem status is indirectly confirmed by the fact that STAT3 phosphorylation under the influence of IL-6 family members IL-11 and Oncostatin M (OSM) contributes to WIHN ( Nelson et al, 2016b _B). There is experimental evidence that TA isoforms of stem/progenitor marker p63, which expression is affected by IL-6/STAT3, are involved both in the inhibition of keratinocytes ability to differentiate and in the stimulation of WIHN ( Nelson et al, 2016a _A).…”

Section: Episc Plasticity During Wound Healing Under the Influence Ofmentioning

confidence: 99%

Epidermal Stem Cells in Hair Follicle Cycling and Skin Regeneration: A View From the Perspective of Inflammation

Morgun

Vorotelyak

2020

Front. Cell Dev. Biol.

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“…Previous data revealed that the IL-6-p-STAT3 pathway was activated during SO 2 -induced airway injury in mice and that STAT3 activation in basal cells regulated ciliogenesis through tyrosine phosphorylation (40). IL-6-p-STAT3-pathway activation modulated expression of the p63 isoform in keratinocytes during regeneration associated with wound healing (41). In this study, we found that hyperphosphorylation of STAT3, attributed to excessive IL-6 secretion, inhibited p63 expression in BLM-induced ALI, whereas MSC SLP increased p63 expression by suppressing excessive activation of IL-6 and p-STAT3.…”

Section: Discussionmentioning

confidence: 99%

“…6a, b). Considering that IL-6 appeared to promote STAT3 phosphorylation in basal cells of the airways and previous data showed that the IL-6-p-STAT3 pathway regulated p63 isoform expression in keratinocytes (40,41), we hypothesized that a sharp rise of IL-6 boosted STAT3 phosphorylation and then restrained p63 expression in BLM-induced ALI. Our results suggested that MSC SLP activated p63 by inhibiting the IL-6-p-STAT3 pathway.…”

Section: Msc Slp Depressed Il-6 Secretion Induced By Blmmentioning

confidence: 96%

Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6–p-STAT3–p63–JAG2 pathway

Peng

Chang

et al. 2020

Preprint

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Background: Mesenchymal stem cells (MSCs) may contribute to repair in severe diseases including acute lung injury (ALI). However, applications with MSCs have been restricted due to safety considerations and limitations in terms of large-scale production and industrial delivery. Alternatively, the MSC secretome has been considered promising for use in therapeutic approaches and has been advanced to pre-clinical and clinical trials. Furthermore, the MSC secretome can be freeze-dried into a stable and ready-to-use supernatant lyophilized powder (SLP) form.Methods: Intratracheal bleomycin was used to induce ALI in mice, and intratracheal MSC SLP was delivered as a treatment. Histopathological assessment was achieved by hematoxylin and eosin, immunohistochemistry, and immunofluorescence staining. Apoptosis, inflammatory infiltration, immunological cell counts, cytokine levels, and mRNA- and protein-expression levels of relevant targets were measured by performing terminal deoxynucleotidyl transferase dUTP nick-end labeling assays, determining total cell and protein levels in bronchoalveolar lavage fluids, flow cytometry, multiple cytokine-detection techniques, and reverse transcriptase-quantitative polymerase chain reaction and western blot analysis, respectively. Plasma lipid profiles were detected by performing lipidomics analysis.Results: Here, we found that intratracheal MSC SLP considerably promoted cell survival, inhibited epithelial cell apoptosis, attenuated inflammatory cell recruitment, and reversed immunological imbalances induced by bleomycin. MSC SLP inhibited signaling through the interleukin 6–phosphorylated signal transducer and activator of transcription pathway to activate tumor protein 63–jagged 2 signaling in basal cells, suppress T helper 17 cell differentiation, promote p63+ cell proliferation and lung damage repair, and relieve inflammatory responses. Furthermore, MSC SLP significantly reversed changes in plasma lipid profiles caused by bleomycin.Conclusions: MSC SLP ameliorated ALI by activating p63 and promoting p63+ cell proliferation and the repair of damaged epithelial cells. The findings of this study also shed insight into ALI pathogenesis and imply that MSC SLP shows considerable therapeutic promise for treating ALI and acute respiratory distress syndrome. Our findings also suggest that phosphatidylserine has potential for serving as a pharmaceutical or dietary supplement for alleviating ALI.

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Interleukin 6 and STAT3 regulate p63 isoform expression in keratinocytes during regeneration

Cited by 13 publications

References 10 publications

Sulforaphane Inhibits the Acquisition of Tobacco Smoke-Induced Lung Cancer Stem Cell-Like Properties via the IL-6/ΔNp63α/Notch Axis

Sulforaphane Inhibits the Acquisition of Tobacco Smoke-Induced Lung Cancer Stem Cell-Like Properties via the IL-6/ΔNp63α/Notch Axis

Epidermal Stem Cells in Hair Follicle Cycling and Skin Regeneration: A View From the Perspective of Inflammation

Lyophilized powder of mesenchymal stem cell supernatant attenuates acute lung injury through the IL-6–p-STAT3–p63–JAG2 pathway

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