CDKI-73 is a Novel Pharmacological Inhibitor of Rab11 Cargo Delivery and Innate Immune Secretion.
Animals
Cytokines
/ metabolism
Drosophila
/ metabolism
Endosomes
/ drug effects
Fat Body
/ drug effects
Humans
Immunity, Innate
/ drug effects
Inflammation Mediators
/ metabolism
Macrophages
/ drug effects
Membrane Fusion
/ drug effects
Protein Transport
/ drug effects
Pyrimidines
/ pharmacology
Sulfonamides
/ pharmacology
THP-1 Cells
rab GTP-Binding Proteins
/ metabolism
CDKI-73
Drosophila
IL-6
Rab11
TNFα
antimicrobial peptide Drosomycin
endosomes
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
05 02 2020
05 02 2020
Historique:
received:
10
01
2020
revised:
31
01
2020
accepted:
03
02
2020
entrez:
9
2
2020
pubmed:
9
2
2020
medline:
13
2
2021
Statut:
epublish
Résumé
Innate immunity is critical for host defence against pathogen and environmental challenge and this involves the production and secretion of immune mediators, such as antimicrobial peptides and pro-inflammatory cytokines. However, when dysregulated, innate immunity can contribute to multifactorial diseases, including inflammatory rheumatic disorders, type 2 diabetes, cancer, neurodegenerative and cardiovascular diseases and even septic shock. During an innate immune response, antimicrobial peptides and cytokines are trafficked via Rab11 multivesicular endosomes, and then sorted into Rab11 vesicles for traffic to the plasma membrane and secretion. In this study, a cyclin-dependent kinase inhibitor CDKI-73 was used to determine its effect on the innate immune response, based on previously identified targets for this compound. Our results showed that CDKI-73 inhibited the delivery of Rab11 vesicles to the plasma membrane, resulting in the accumulation of large multivesicular Rab11 endosomes near the cell periphery. In addition to the effect on endosome delivery, CDKI-73 down-regulated the amount of innate immune cargo, including the antimicrobial peptide Drosomycin and pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFα). We concluded that CDKI-73 has the potential to regulate the delivery and secretion of certain innate immune cargo, which could be used to control inflammation.
Identifiants
pubmed: 32033486
pii: cells9020372
doi: 10.3390/cells9020372
pmc: PMC7072129
pii:
doi:
Substances chimiques
3-(5-fluoro-4-(4-methyl-2-(methylamino)thiazol-5-yl)pyrimidin-2-ylamino)benzenesulfonamide
0
Cytokines
0
Inflammation Mediators
0
Pyrimidines
0
Sulfonamides
0
rab11 protein
EC 3.6.1.-
rab GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
The authors declare no conflict of interest.
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