Pentacyclic triterpenoid ursolic acid interferes with mast cell activation via a lipid-centric mechanism affecting Fc epsilon RI signalosome functions

0565125 - ÚMG 2023 RIV CZ eng J - Journal Article
Shaik, Gouse Mohiddin - Dráberová, Lubica - Černohouzová, Sára - Tůmová, Magda - Bugajev, Viktor - Dráber, Peter
Pentacyclic triterpenoid ursolic acid interferes with mast cell activation via a lipid-centric mechanism affecting Fc epsilon RI signalosome functions.
Journal of Biological Chemistry. Roč. 28, č. 11 (2022), č. článku 102497. ISSN 0021-9258. E-ISSN 1083-351X
R&D Projects: GA ČR GA20-16481S; GA MPO FV20479; GA TA ČR TP01010060; GA MŠMT(CZ) LM2018129; GA MŠMT(CZ) EF18_046/0016045
Institutional support: RVO:68378050
Keywords : mast cell * immunoglobulin E * lipid raft * plasma membrane * signal transduction * tumor necrosis factor * tyrosine kinase
OECD category: Biochemistry and molecular biology
Impact factor: 4.8, year: 2022
Method of publishing: Open access
https://doi.org/10.1016/j.jbc.2022.102497

Pentacyclic triterpenoids, including ursolic acid (UA), are bioactive compounds with multiple biological activities involving anti-inflammatory effects. However, the mode of their action on mast cells, key players in the early stages of allergic inflammation, and underlying molecular mechanisms remain enigmatic. To better understand the effect of UA on mast cell signaling, here we examined the consequences of short-term treatment of mouse bone marrow-derived mast cells with UA. Using IgE-sensitized and antigen-or thapsigargin-activated cells, we found that 15 min exposure to UA inhibited high affinity IgE receptor (FceRI)-mediated degranulation, calcium response, and extracellular calcium uptake. We also found that UA inhibited migration of mouse bone marrow-derived mast cells toward antigen but not toward prostaglandin E2 and stem cell factor. Compared to control antigen-activated cells, UA enhanced the production of tumor necrosis factor-alpha at the mRNA and protein levels. However, secretion of this cytokine was inhibited. Further analysis showed that UA enhanced tyrosine phosphorylation of the SYK kinase and several other proteins involved in the early stages of FceRI signaling, even in the absence of antigen activation, but inhibited or reduced their further phosphorylation at later stages. In addition, we show that UA induced changes in the properties of detergent-resistant plasma membrane microdomains and reduced antibody-mediated clustering of the FceRI and glycosylphosphatidylinositol-anchored protein Thy1. Finally, UA inhibited mobility of the FceRI and cholesterol. These combined data suggest that UA exerts its effects, at least in part, via lipid-centric plasma membrane perturbations, hence affecting the functions of the FceRI signalosome.
Permanent Link: https://hdl.handle.net/11104/0338307