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A Novel Role of Numb as A Regulator of Pro-inflammatory Cytokine Production in Macrophages in Response to Toll-like Receptor 4
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Metadata
Document Title
A Novel Role of Numb as A Regulator of Pro-inflammatory Cytokine Production in Macrophages in Response to Toll-like Receptor 4
Author
Kueanjinda P., Roytrakul S., Palaga T.
Name from Authors Collection
Affiliations
Interdisciplinary Program in Medical Microbiology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand; Center of Excellence in Immunology and Immune-mediated Diseases, Chulalongkorn University, Bangkok, 10330, Thailand; National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathum Thani, Thailand; Department of Microbiology, Omics Sciences and Bioinformatics Center Faculty of Science, Chulalongkorn University, Bangkok, 10330, Thailand
Type
Article
Source Title
Scientific Reports
ISSN
20452322
Year
2015
Volume
5
Open Access
Gold, Green
Publisher
Nature Publishing Group
DOI
10.1038/srep12784
Abstract
Activation of macrophages triggers the release of pro-inflammatory cytokines leading to inflammation. Numb is a negative regulator of Notch signaling, but the role of Numb in macrophages is not fully understood. In this study, the role of Numb as a regulator of inflammatory responses in macrophages was investigated. Murine bone marrow-derived macrophages, in which expression of Numb was silenced, secreted significantly less TNFα, IL-6 and IL-12 and more IL-10 upon activation by lipopolysaccharide (LPS), a ligand for Toll-like receptor 4 (TLR4), despite increased Notch signaling. The Tnfα mRNA levels both in Numb-deficient and wild-type macrophages were not significantly different, unlike those of Il6 and Il12-p40. In Numb-deficient macrophages, the Tnfα mRNAs were degraded at faster rate, compared to those in control macrophages. Activation of p38 MAPK and NF-κB p65 were compromised in activated Numb deficient macrophages. Numb was found to interact with the E3 ubiquitin ligase, Itch, which reportedly regulates p38 MAPK. In addition, blocking the Notch signaling pathway in activated, Numb-deficient macrophages did not further reduce TNFα levels, suggesting a Notch-independent role for Numb. A proteomics approach revealed a novel funciton for Numb in regulating complex signaling cascades downstream of TLRs, partially involving Akt/NF-κB p65/p38 MAPK in macrophages.
Funding Sponsor
Chulalongkorn University
License
CC BY
Rights
Author
Publication Source
Scopus