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Negative regulatory roles of ORMDL3 in the Fc epsilon RI-triggered expression of proinflammatory mediators and chemotactic response in murine mast cells
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SYSNO ASEP 0471890 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Negative regulatory roles of ORMDL3 in the Fc epsilon RI-triggered expression of proinflammatory mediators and chemotactic response in murine mast cells Author(s) Bugajev, Viktor (UMG-J) RID
Hálová, Ivana (UMG-J) RID, ORCID
Dráberová, Lubica (UMG-J) RID
Bambousková, Monika (UMG-J)
Potůčková, Lucie (UMG-J)
Dráberová, Helena (UMG-J)
Paulenda, Tomáš (UMG-J)
Junyent, Sergi (UMG-J)
Dráber, Petr (UMG-J) RIDNumber of authors 9 Source Title Cellular and Molecular Life Sciences - ISSN 1420-682X
Roč. 73, č. 6 (2016), s. 1265-1285Number of pages 21 s. Language eng - English Country CH - Switzerland Keywords Mast cell interference ; ORMDL3 knockdown ; Prostalglandin D2 ; Degranulation ; Chemotaxis ; Proinflammatory cytokines Subject RIV EB - Genetics ; Molecular Biology R&D Projects GA14-00703S GA ČR - Czech Science Foundation (CSF) GBP302/12/G101 GA ČR - Czech Science Foundation (CSF) GA14-09807S GA ČR - Czech Science Foundation (CSF) Institutional support UMG-J - RVO:68378050 UT WOS 000371079200011 DOI https://doi.org/10.1007/s00018-015-2047-3 Annotation Single-nucleotide polymorphism studies have linked the chromosome 17q12-q21 region, where the human orosomucoid-like (ORMDL)3 gene is localized, to the risk of asthma and several other inflammatory diseases. Although mast cells are involved in the development of these diseases, the contribution of ORMDL3 to the mast cell physiology is unknown. In this study, we examined the role of ORMDL3 in antigen-induced activation of murine mast cells with reduced or enhanced ORMDL3 expression. Our data show that in antigen-activated mast cells, reduced expression of the ORMDL3 protein had no effect on degranulation and calcium response, but significantly enhanced phosphorylation of AKT kinase at Ser 473 followed by enhanced phosphorylation and degradation of I kappa B alpha and translocation of the NF-kappa B p65 subunit into the nucleus. These events were associated with an increased expression of proinflammatory cytokines (TNF-alpha, IL-6, and IL-13), chemokines (CCL3 and CCL4), and cyclooxygenase-2 dependent synthesis of prostaglandin D2. Antigen-mediated chemotaxis was also enhanced in ORMDL3-deficient cells, whereas spreading on fibronectin was decreased. On the other hand, increased expression of ORMDL3 had no significant effect on the studied signaling events, except for reduced antigen-mediated chemotaxis. These data were corroborated by increased IgE-antigen-dependent passive cutaneous anaphylaxis in mice with locally silenced ORMDL3 using short interfering RNAs. Our data also show that antigen triggers suppression of ORMDL3 expression in the mast cells. In summary, we provide evidence that downregulation of ORMDL3 expression in mast cells enhances AKT and NF-kappa B-directed signaling pathways and chemotaxis and contributes to the development of mast cell-mediated local inflammation in vivo. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2017
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