Browsing by Subject "epithelial integrity"

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  • Rajakylä, Eeva Kaisa; Lehtimäki, Jaakko I.; Acheva, Anna; Schaible, Niccole; Lappalainen, Pekka; Krishnan, Ramaswamy; Tojkander, Sari (2020)
    Summary Defects in the maintenance of intercellular junctions are associated with loss of epithelial barrier function and consequent pathological conditions, including invasive cancers. Epithelial integrity is dependent on actomyosin bundles at adherens junctions, but the origin of these junctional bundles is incompletely understood. Here we show that peripheral actomyosin bundles can be generated from a specific actin stress fiber subtype, transverse arcs, through their lateral fusion at cell-cell contacts. Importantly, we find that assembly and maintenance of peripheral actomyosin bundles are dependent on the mechanosensitive CaMKK2/AMPK signaling pathway and that inhibition of this route leads to disruption of tension-maintaining actomyosin bundles and re-growth of stress fiber precursors. This results in redistribution of cellular forces, defects in monolayer integrity, and loss of epithelial identity. These data provide evidence that the mechanosensitive CaMKK2/AMPK pathway is critical for the maintenance of peripheral actomyosin bundles and thus dictates cell-cell junctions through cellular force distribution.
  • Unbiased Biomarkers Prediction Re; Jevnikar, Zala; Östling, Jörgen; Vaarala, Outi (2019)
    Background: Although several studies link high levels of IL-6 and soluble IL-6 receptor (sIL-6R) to asthma severity and decreased lung function, the role of IL-6 trans-signaling (IL-6TS) in asthmatic patients is unclear. Objective: We sought to explore the association between epithelial IL-6TS pathway activation and molecular and clinical phenotypes in asthmatic patients. Methods: An IL-6TS gene signature obtained from air-liquid interface cultures of human bronchial epithelial cells stimulated with IL-6 and sIL-6R was used to stratify lung epithelial transcriptomic data (Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes [U-BIOPRED] cohorts) by means of hierarchical clustering. IL-6TS-specific protein markers were used to stratify sputum biomarker data (Wessex cohort). Molecular phenotyping was based on transcriptional profiling of epithelial brushings, pathway analysis, and immunohistochemical analysis of bronchial biopsy specimens. Results: Activation of IL-6TS in air-liquid interface cultures reduced epithelial integrity and induced a specific gene signature enriched in genes associated with airway remodeling. The IL-6TS signature identified a subset of patients with IL-6TS-high asthma with increased epithelial expression of IL-6TS-inducible genes in the absence of systemic inflammation. The IL-6TS-high subset had an overrepresentation of frequent exacerbators, blood eosinophilia, and submucosal infiltration of T cells and macrophages. In bronchial brushings Toll-like receptor pathway genes were upregulated, whereas expression of cell junction genes was reduced. Sputum sIL-6R and IL-6 levels correlated with sputum markers of remodeling and innate immune activation, in particular YKL-40, matrix metalloproteinase 3, macrophage inflammatory protein 1 beta, IL-8, and IL-1 beta. Conclusions: Local lung epithelial IL-6TS activation in the absence of type 2 airway inflammation defines a novel subset of asthmatic patients and might drive airway inflammation and epithelial dysfunction in these patients.
  • DIABIMMUNE Study Grp; Reinert-Hartwall, Linnea; Siljander, Heli; Härkönen, Taina; Vatanen, Tommi; Ilonen, Jorma; Niemelä, Onni; Luopajärvi, Kristiina; Dorshakova, Natalya; Mokurov, Sergei; Peet, Aleksandr; Tillmann, Vallo; Uibo, Raivo; Knip, Mikael; Vaarala, Outi; Honkanen, Jarno (2022)
    Background Decreased exposure to microbial agents in industrialized countries and urban living areas is considered as a risk factor of developing immune-mediated diseases, such as allergies and asthma. Epithelial surfaces in the gastrointestinal and respiratory tracts and in the skin constitute the primary areas in contact with the environmental microbial load. Methods We analyzed the levels of 30 cytokines and growth factors in serum or plasma as markers of the immune maturation in the participants in the DIABIMMUNE study from Russian Karelia (n = 60), Estonia (n = 83) and Finland (n = 89), three neighboring countries with remarkable differences in the incidences of allergies, asthma and autoimmune diseases. Results We observed an upregulation of T helper cell signature cytokines during the first 12 months of life, reflecting natural development of adaptive immune responses. During the first years of life, circulating concentrations of epidermal growth factor (EGF) were significantly higher, especially in Russian children compared with Finnish children. The children who developed IgE sensitization showed lower levels of EGF than those without such responses. Conclusion Our results suggest that low circulating EGF levels associate with the risk of allergies possibly via the effects on the epithelial integrity and mucosal homeostasis.
  • Virkunen, Ekaterina (Helsingin yliopisto, 2018)
    The majority of cancers, such as breast cancer, originate from epithelial structures. Highly organized epithelial tissues are comprised of cells which manifest apico-basal polarization. Factors regulating apico-basal polarity and epithelial integrity are often observed deregulated in cancer cells and loss of polarity is often observed in tumors. However, the importance and the specific role of epithelial integrity regulators in tumorigenesis are still not fully defined. This study shows that the key regulators of epithelial cell polarity Par6B and Par6G proteins have a role in the restriction of cell proliferation in mammary epithelial cell lines. Using the shRNA silencing approach, downregulation of PARD6B and PARD6G in the cells lead to the impediment of the cell-cycle exit, verified in proliferation suppressive conditions in which cells normally would enter quiescence. Par6 proteins were shown to regulate cell proliferation via the canonical PI3K/Akt pathway, which is one of the most commonly deregulated cell proliferation promoting pathways in cancer cells. The results demonstrate the unknown function of Par6B and Par6G proteins as cell proliferation regulators and a previously unrecognized relation between Par6 proteins and PI3K/Akt pathway. However, the detailed interaction between Par6 proteins and the PI3K/Akt pathway ought to be investigated further. In addition, the results revealed that Par6 proteins have different effects on cell proliferation suggesting biological differences between Par6 proteins and that certainly bears further investigation. In conclusion, the study presents a previously unknown connection between epithelial integrity regulators and cancer-relevant cell proliferation promoting pathways, which may provide new targets for therapeutic intervention in the future.