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1.
PLoS One ; 7(8): e43545, 2012.
Article in English | MEDLINE | ID: mdl-22970103

ABSTRACT

INTRODUCTION: Chronic mast cell activation is a characteristic feature of asthma. BEAS-2B human airway epithelial cells (AEC) profoundly inhibit both constitutive and IgE-dependent human lung mast cell (HLMC) histamine release. The aim of this study was to examine the regulation of HLMC degranulation by primary AEC from healthy and asthmatic subjects, and investigate further the inhibitory mechanism. METHODS: HLMC were co-cultured with both BEAS-2B and primary AEC grown as monolayers or air-liquid interface (ALI) cultures. RESULTS: Both constitutive and IgE-dependent HLMC histamine release were attenuated by BEAS-2B, primary AEC monolayers and ALI cultures. This occurred in the absence of HLMC-AEC contact indicating the presence of a soluble factor. Unlike healthy ALI AEC, asthmatic ALI-AEC did not significantly reduce constitutive histamine release. AEC inhibitory activity was transferable in primary AEC monolayer supernatant, but less active than with Transwell co-culture, suggesting that the inhibitory factor was labile. The AEC inhibitory effects were attenuated by both AEC wounding and pertussis toxin, indicating the involvement of a G(0)/G(i) receptor coupled mechanism. Solid phase extraction of lipids (<10 kDa) removed the AEC inhibitory activity. The lipid derivatives resolving D1 and D2 and lipoxin A(4) attenuated HLMC histamine release in a dose-dependent fashion but were not detectable in co-culture supernatants. CONCLUSIONS: Primary AEC suppress HLMC constitutive and IgE-dependent histamine secretion through the release of a soluble, labile lipid mediator(s) that signals through the G(0)/G(i) receptor coupled mechanism. Manipulation of this interaction may have a significant therapeutic role in asthma.


Subject(s)
Cell Degranulation , Epithelial Cells/physiology , Lung/pathology , Mast Cells/physiology , Respiratory Mucosa/pathology , Asthma/pathology , Cells, Cultured , Coculture Techniques , Docosahexaenoic Acids/metabolism , Docosahexaenoic Acids/pharmacology , Docosahexaenoic Acids/physiology , Epithelial Cells/drug effects , Histamine Release , Humans , Immunoglobulin E/physiology , Inflammation Mediators/metabolism , Limit of Detection , Lipoxins/metabolism , Lipoxins/pharmacology , Lipoxins/physiology , Mast Cells/drug effects , Mast Cells/metabolism , Paracrine Communication , Pertussis Toxin/pharmacology , Receptors, Prostaglandin E, EP2 Subtype/antagonists & inhibitors , Receptors, Prostaglandin E, EP2 Subtype/metabolism , Xanthones/pharmacology
2.
Proc Natl Acad Sci U S A ; 106(35): 14884-9, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19706487

ABSTRACT

The epithelial-mesenchymal transition (EMT) contributes to cancer metastasis. Two ZEB family members, ZEB1 and ZEB2(SIP1), inhibit transcription of the E-cadherin gene and induce EMT in vitro. However, their relevance to human cancer is insufficiently studied. Here, we performed a comparative study of SIP1 and ZEB1 proteins in cancer cell lines and in one form of human malignancy, carcinoma of the bladder. Whereas ZEB1 protein was expressed in all E-cadherin-negative carcinoma cell lines, being in part responsible for the high motility of bladder cancer cells, SIP1 was hardly ever detectable in carcinoma cells in culture. However, SIP1 represented an independent factor of poor prognosis (P = 0.005) in a series of bladder cancer specimens obtained from patients treated with radiotherapy. In contrast, ZEB1 was rarely expressed in tumor tissues; and E-cadherin status did not correlate with the patients' survival. SIP1 protected cells from UV- and cisplatin-induced apoptosis in vitro but had no effect on the level of DNA damage. The anti-apoptotic effect of SIP1 was independent of either cell cycle arrest or loss of cell-cell adhesion and was associated with reduced phosphorylation of ATM/ATR targets in UV-treated cells. The prognostic value of SIP1 and its role in DNA damage response establish a link between genetic instability and metastasis and suggest a potential importance for this protein as a therapeutic target. In addition, we conclude that the nature of an EMT pathway rather than the deregulation of E-cadherin per se is critical for the progression of the disease and patients' survival.


Subject(s)
Apoptosis , DNA Damage , Homeodomain Proteins/metabolism , Repressor Proteins/metabolism , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/metabolism , Cadherins/metabolism , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Homeodomain Proteins/genetics , Humans , Neoplasm Invasiveness , Phenotype , Prognosis , Repressor Proteins/genetics , Survival Rate , Transcription Factors/metabolism , Treatment Outcome , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/radiotherapy , Zinc Finger E-box Binding Homeobox 2 , Zinc Finger E-box-Binding Homeobox 1
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