TAK1 signaling activity links the mast cell cytokine response and degranulation in allergic inflammation.

Autor: Watson CJF; Department of Health Sciences, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada., Maguire ARR; Department of Health Sciences, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada., Rouillard MM; Department of Health Sciences, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada., Crozier RWE; Department of Health Sciences, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada., Yousef M; Department of Health Sciences, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada., Bruton KM; Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada., Fajardo VA; Department of Kinesiology, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada., MacNeil AJ; Department of Health Sciences, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada.
Jazyk: angličtina
Zdroj: Journal of leukocyte biology [J Leukoc Biol] 2020 Apr; Vol. 107 (4), pp. 649-661. Date of Electronic Publication: 2020 Feb 28.
DOI: 10.1002/JLB.2A0220-401RRR
Abstrakt: Mast cells drive the inappropriate immune response characteristic of allergic inflammatory disorders via release of pro-inflammatory mediators in response to environmental cues detected by the IgE-FcεRI complex. The role of TGF-β-activated kinase 1 (TAK1), a participant in related signaling in other contexts, remains unknown in allergy. We detect novel activation of TAK1 at Ser412 in response to IgE-mediated activation under SCF-c-kit potentiation in a mast cell-driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor 5Z-7-oxozeaenol (OZ). We, therefore, interrogated the role of TAK1 in a series of mast cell-mediated responses using IgE-sensitized murine bone marrow-derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition by OZ resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NF-κB pathway via IκBα. Impaired gene expression and near abrogation in release of pro-inflammatory cytokines TNF, IL-6, IL-13, and chemokines CCL1, and CCL2 was detected. Finally, a significant inhibition of mast cell degranulation, accompanied by an impairment in calcium mobilization, was observed in TAK1-inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NF-κB pathways in driving the late-phase response, but also initiation of the degranulation mechanism of the mast cell early-phase response following allergen recognition and may warrant consideration in future therapeutic development.
(©2020 Society for Leukocyte Biology.)
Databáze: MEDLINE
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