Tumor NLRP3-Derived IL-1β Drives the IL-6/STAT3 Axis Resulting in Sustained MDSC-Mediated Immunosuppression.
Animals
Cell Line, Tumor
Humans
Immune Tolerance
/ drug effects
Interleukin-1beta
/ immunology
Interleukin-6
/ immunology
Melanoma
/ immunology
Melanoma, Experimental
/ drug therapy
Mice, Inbred C57BL
Mice, Knockout
Models, Immunological
Myeloid-Derived Suppressor Cells
/ immunology
NLR Family, Pyrin Domain-Containing 3 Protein
/ immunology
Nitriles
/ pharmacology
Pyrazoles
/ pharmacology
Pyrimidines
/ pharmacology
STAT3 Transcription Factor
/ immunology
Signal Transduction
/ drug effects
Tumor Burden
/ drug effects
NLRP3
interleukin-1β
interleukin-6
myeloid-derived suppressor cells
signal transducer and activator of transcription 3
Journal
Frontiers in immunology
ISSN: 1664-3224
Titre abrégé: Front Immunol
Pays: Switzerland
ID NLM: 101560960
Informations de publication
Date de publication:
2021
2021
Historique:
received:
30
01
2021
accepted:
09
08
2021
entrez:
17
9
2021
pubmed:
18
9
2021
medline:
21
10
2021
Statut:
epublish
Résumé
Tumors evade the immune system by inducing inflammation. In melanoma, tumor-derived IL-1β drives inflammation and the expansion of highly immunosuppressive myeloid-derived suppressor cells (MDSCs). Similar in many tumors, melanoma is also linked to the downstream IL-6/STAT3 axis. In this study, we observed that both recombinant and tumor-derived IL-1β specifically induce pSTAT3(Y705), creating a tumor-autoinflammatory loop, which amplifies IL-6 signaling in the human melanoma cell line 1205Lu. To disrupt IL-1β/IL-6/STAT3 axis, we suppressed IL-1β-mediated inflammation by inhibiting the NOD-like receptor protein 3 (NLRP3) using OLT1177, a safe-in-humans specific NLRP3 oral inhibitor.
Identifiants
pubmed: 34531850
doi: 10.3389/fimmu.2021.661323
pmc: PMC8438323
doi:
Substances chimiques
AZD 1480
0
Interleukin-1beta
0
Interleukin-6
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Nitriles
0
Pyrazoles
0
Pyrimidines
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
dapansutrile
2Z03364G96
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
661323Subventions
Organisme : NIAID NIH HHS
ID : R01 AI015614
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125595
Pays : United States
Informations de copyright
Copyright © 2021 Tengesdal, Dinarello, Powers, Burchill, Joosten, Marchetti and Dinarello.
Déclaration de conflit d'intérêts
LJ serves on Olatec’s Scientific Advisory Board and receives compensation. CD serves as Chairman of Olatec’s Scientific Advisory Board, is co-Chief Scientific Officer, receives compensation and has equity in Olatec. CM serves as Director for Olatec’s Innovative Science Program and has equity in Olatec. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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