Loss of IL-10 signaling in macrophages limits bacterial killing driven by prostaglandin E2.
Cell Differentiation
/ genetics
Cells, Cultured
Dinoprostone
/ antagonists & inhibitors
Female
Gene Knockout Techniques
Humans
Induced Pluripotent Stem Cells
/ metabolism
Inflammation
/ chemically induced
Inflammatory Bowel Diseases
/ metabolism
Interleukin-10
/ metabolism
Interleukin-10 Receptor alpha Subunit
/ genetics
Interleukin-10 Receptor beta Subunit
/ genetics
Lipopolysaccharides
/ pharmacology
Macrophage Activation
/ drug effects
Macrophages
/ drug effects
Mutation
Phosphorylation
/ genetics
STAT3 Transcription Factor
/ metabolism
Salmonella typhimurium
/ metabolism
Signal Transduction
/ drug effects
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
03 02 2020
03 02 2020
Historique:
received:
05
04
2018
revised:
09
06
2019
accepted:
25
10
2019
entrez:
11
12
2019
pubmed:
11
12
2019
medline:
10
9
2020
Statut:
ppublish
Résumé
Loss of IL-10 signaling in macrophages (Mφs) leads to inflammatory bowel disease (IBD). Induced pluripotent stem cells (iPSCs) were generated from an infantile-onset IBD patient lacking a functional IL10RB gene. Mφs differentiated from IL-10RB-/- iPSCs lacked IL-10RB mRNA expression, were unable to phosphorylate STAT3, and failed to reduce LPS induced inflammatory cytokines in the presence of exogenous IL-10. IL-10RB-/- Mφs exhibited a striking defect in their ability to kill Salmonella enterica serovar Typhimurium, which was rescuable after experimentally introducing functional copies of the IL10RB gene. Genes involved in synthesis and receptor pathways for eicosanoid prostaglandin E2 (PGE2) were more highly induced in IL-10RB-/- Mφs, and these Mφs produced higher amounts of PGE2 after LPS stimulation compared with controls. Furthermore, pharmacological inhibition of PGE2 synthesis and PGE2 receptor blockade enhanced bacterial killing in Mφs. These results identify a regulatory interaction between IL-10 and PGE2, dysregulation of which may drive aberrant Mφ activation and impaired host defense contributing to IBD pathogenesis.
Identifiants
pubmed: 31819956
pii: 132614
doi: 10.1084/jem.20180649
pmc: PMC7041704
pii:
doi:
Substances chimiques
IL10 protein, human
0
IL10RB protein, human
0
Interleukin-10 Receptor alpha Subunit
0
Interleukin-10 Receptor beta Subunit
0
Lipopolysaccharides
0
STAT3 Transcription Factor
0
STAT3 protein, human
0
Interleukin-10
130068-27-8
Dinoprostone
K7Q1JQR04M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2019 Mukhopadhyay et al.
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