Inhibition of allergen-mediated mast cell activation by TAK1 inhibitor 5Z-7-oxozeaenol
dc.contributor.author | Watson, Colton JF | |
dc.date.accessioned | 2017-09-14T19:51:46Z | |
dc.date.available | 2017-09-14T19:51:46Z | |
dc.identifier.uri | http://hdl.handle.net/10464/12992 | |
dc.description.abstract | Introduction & Aim: Allergic inflammatory disorders are at epidemic levels worldwide. Mast cells drive this inappropriate immune response via release of a variety of pro-inflammatory mediators in response to environmental cues detected by the IgE-FcεRI complex, but we do not fully understand the contributing molecular mechanisms. Transforming growth factor β-activated kinase 1 (TAK1) is a known participant in related signaling through MAPK and NF-κB; however the role of TAK1 in IgE-FcεRI signaling and resultant allergic inflammation remains unknown. We aim to assess the role of TAK1 in IgE-mediated mast cell activation. Methods: Bone marrow-derived mast cells were sensitized with allergen-specific IgE and treated with the corresponding allergen for various times in the presence or absence of 5Z-7-oxozeaenol. Mast cell signaling was measured by western blotting, induced gene expression by qPCR, pro-inflammatory mediator release by ELISA and mast cell degranulation by β-hexosaminidase release assay. Results: TAK1-inhibition resulted in significant impairment in the phosphorylation of various MAPKs (p38, ERK and JNK) as well as NF-κB pathway kinase IκBα. Impaired gene expression of pro-inflammatory cytokines IL-4, IL-6, IL-13, and chemokines CCL1, -2, and -3 were detected. Furthermore, a drastic decrease in the concentration of pro-inflammatory cytokines, IL-6 and TNF, and chemokines CCL1 and CCL2, in stimulated cell supernatants was detected. Finally, a significant inhibition of mast cell degranulation was also observed in the TAK1-inhibited cells. Conclusion and Significance: These results suggest that TAK1 acts as a signaling node linking the MAPK and NF-κB pathways in mast cells responding to allergen and may warrant consideration in future therapeutic development. | en_US |
dc.language.iso | eng | en_US |
dc.publisher | Brock University | en_US |
dc.subject | Allergy | en_US |
dc.subject | Mast Cell | en_US |
dc.subject | 5Z-7-oxozeaenol | en_US |
dc.subject | Transforming growth factor-beta-activated kinase 1 (TAK1) | en_US |
dc.subject | Inflammation | en_US |
dc.title | Inhibition of allergen-mediated mast cell activation by TAK1 inhibitor 5Z-7-oxozeaenol | en_US |
dc.type | Electronic Thesis or Dissertation | en |
dc.degree.name | M.Sc. Applied Health Sciences | en_US |
dc.degree.level | Masters | en_US |
dc.contributor.department | Applied Health Sciences Program | en_US |
dc.degree.discipline | Faculty of Applied Health Sciences | en_US |
refterms.dateFOA | 2018-09-14T00:00:00Z |