PMID- 36608933
OWN - NLM
STAT- MEDLINE
DCOM- 20230517
LR  - 20230517
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 299
IP  - 4
DP  - 2023 Apr
TI  - Carnosic acid inhibits secretion of allergic inflammatory mediators in 
      IgE-activated mast cells via direct regulation of Syk activation.
PG  - 102867
LID - S0021-9258(22)01310-2 [pii]
LID - 10.1016/j.jbc.2022.102867 [doi]
LID - 102867
AB  - Mast cells are essential regulators of inflammation most recognized for their 
      central role in allergic inflammatory disorders. Signaling via the high-affinity 
      immunoglobulin E (IgE) receptor, FcepsilonRI, leads to rapid degranulation of preformed 
      granules and the sustained release of newly synthesized proinflammatory 
      mediators. Our group recently established rosemary extract as a potent regulator 
      of mast cell functions, attenuating MAPK and NF-kappaB signaling. Carnosic acid 
      (CA)-a major polyphenolic constituent of rosemary extract-has been shown to 
      exhibit anti-inflammatory effects in other immune cell models, but its role as a 
      potential modulator of mast cell activation is undefined. Therefore, we sought 
      here to determine the modulatory effects of CA in a mast cell model of allergic 
      inflammation. We sensitized bone marrow-derived mast cells with 
      anti-trinitrophenyl IgE and activated with allergen (TNP-BSA) under stem cell 
      factor potentiation, in addition to treatment with CA. Our results indicate that 
      CA significantly inhibits allergen-induced early phase responses including Ca(2+) 
      mobilization, ROS production, and subsequent degranulation. We also show CA 
      treatment reduced late phase responses, including the release of all cytokines 
      and chemokines examined following IgE stimulation and corresponding gene 
      expression excepting that of CCL2. Importantly, we determined that CA mediates 
      its inhibitory effects through modulation of tyrosine kinase Syk and downstream 
      effectors TAK1 (Ser412) and Akt (Ser473) as well as NFkappaB signaling, while 
      phosphorylation of FcepsilonRI (gamma chain) and MAPK proteins remained unaltered. These 
      novel findings establish CA as a potent modulator of mast cell activation, 
      warranting further investigation as a putative anti-allergy therapeutic.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Crozier, Robert W E
AU  - Crozier RWE
AD  - Department of Health Sciences, Brock University, St Catharines, Ontario, Canada.
FAU - Yousef, Michael
AU  - Yousef M
AD  - Department of Health Sciences, Brock University, St Catharines, Ontario, Canada.
FAU - Coish, Jeremia M
AU  - Coish JM
AD  - Department of Health Sciences, Brock University, St Catharines, Ontario, Canada.
FAU - Fajardo, Val A
AU  - Fajardo VA
AD  - Department of Kinesiology, Brock University, St Catharines, Ontario, Canada.
FAU - Tsiani, Evangelia
AU  - Tsiani E
AD  - Department of Health Sciences, Brock University, St Catharines, Ontario, Canada.
FAU - MacNeil, Adam J
AU  - MacNeil AJ
AD  - Department of Health Sciences, Brock University, St Catharines, Ontario, Canada. 
      Electronic address: amacneil@brocku.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230103
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Allergens)
RN  - 37341-29-0 (Immunoglobulin E)
RN  - 0 (Inflammation Mediators)
RN  - 0 (NF-kappa B)
RN  - 0 (Receptors, IgE)
RN  - LI791SXT24 (salvin)
RN  - EC 2.7.10.2 (Syk Kinase)
RN  - EC 2.7.10.2 (SYK protein, human)
RN  - 0 (Abietanes)
SB  - IM
MH  - Humans
MH  - Allergens
MH  - Cell Degranulation
MH  - *Hypersensitivity
MH  - Immunoglobulin E
MH  - Inflammation/metabolism
MH  - *Inflammation Mediators/metabolism
MH  - *Mast Cells/drug effects/metabolism
MH  - NF-kappa B/metabolism
MH  - Receptors, IgE/metabolism
MH  - Syk Kinase/metabolism
MH  - *Abietanes/pharmacology
PMC - PMC10068559
OTO - NOTNLM
OT  - IgE
OT  - allergy
OT  - chemokine
OT  - cytokine
OT  - degranulation
OT  - inflammation
OT  - polyphenol
COIS- Conflicts of interest The authors declare no conflict of interest.
EDAT- 2023/01/08 06:00
MHDA- 2023/04/28 06:41
PMCR- 2023/01/03
CRDT- 2023/01/07 16:06
PHST- 2022/07/15 00:00 [received]
PHST- 2022/12/22 00:00 [revised]
PHST- 2022/12/29 00:00 [accepted]
PHST- 2023/04/28 06:41 [medline]
PHST- 2023/01/08 06:00 [pubmed]
PHST- 2023/01/07 16:06 [entrez]
PHST- 2023/01/03 00:00 [pmc-release]
AID - S0021-9258(22)01310-2 [pii]
AID - 102867 [pii]
AID - 10.1016/j.jbc.2022.102867 [doi]
PST - ppublish
SO  - J Biol Chem. 2023 Apr;299(4):102867. doi: 10.1016/j.jbc.2022.102867. Epub 2023 
      Jan 3.