Dickkopf1 fuels inflammatory cytokine responses.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
20 12 2022
20 12 2022
Historique:
received:
25
07
2022
accepted:
12
12
2022
entrez:
20
12
2022
pubmed:
21
12
2022
medline:
23
12
2022
Statut:
epublish
Résumé
Many human diseases, including cancer, share an inflammatory component but the molecular underpinnings remain incompletely understood. We report that physiological and pathological Dickkopf1 (DKK1) activity fuels inflammatory cytokine responses in cell models, mice and humans. DKK1 maintains the elevated inflammatory tone of cancer cells and is required for mounting cytokine responses following ligation of toll-like and cytokine receptors. DKK1-controlled inflammation derives from cell-autonomous mechanisms, which involve SOCS3-restricted, nuclear RelA (p65) activity. We translate these findings to humans by showing that genetic DKK1 variants are linked to elevated cytokine production across healthy populations. Finally, we find that genetic deletion of DKK1 but not pharmacological neutralization of soluble DKK1 ameliorates inflammation and disease trajectories in a mouse model of endotoxemia. Collectively, our study identifies a cell-autonomous function of DKK1 in the control of the inflammatory response, which is conserved between malignant and non-malignant cells. Additional studies are required to mechanistically dissect cellular DKK1 trafficking and signaling pathways.
Identifiants
pubmed: 36539532
doi: 10.1038/s42003-022-04368-8
pii: 10.1038/s42003-022-04368-8
pmc: PMC9765382
doi:
Substances chimiques
Cytokines
0
Intercellular Signaling Peptides and Proteins
0
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
1391Subventions
Organisme : NIAID NIH HHS
ID : K08 AI128745
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR007107
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Informations de copyright
© 2022. The Author(s).
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