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Endogenous prostaglandin E2 potentiates anti-inflammatory phenotype of macrophage through the CREB-C/EBP-β cascade.
- Source :
-
European journal of immunology [Eur J Immunol] 2015 Sep; Vol. 45 (9), pp. 2661-71. Date of Electronic Publication: 2015 Jul 20. - Publication Year :
- 2015
-
Abstract
- Macrophages have important functions in tissue homeostasis, but the exact mechanisms regarding wide spectrum of macrophage phenotype remain unresolved. In this study, we report that mouse bone marrow derived naïve macrophages produce prostaglandin E2 (PGE2 ) endogenously, resulting in anti-inflammatory gene expression upon differentiation induced by macrophage colony stimulating factor (M-CSF). Cyclooxygenase (COX) inhibition by indomethacin reduced endogenous PGE2 production of macrophages and subsequently reduced arg1, IL10 and Mrc1, YmI and FizzI gene expressions. Of note, PGE2 phosphorylates CREB via EP2 and EP4 receptor ligation, thereby transcriptionally increasing C/EBP-β expression in BALB/c bone marrow derived macrophages. Activated CREB directly binds to the CREB-responsive element of the C/EBP-β promoter, such that PGE2 ultimately reinforces arg1, IL10 and Mrc1 gene expression. Cyclic AMP activator forskolin also phosphorylated CREB and induced the C/EBP-β cascade, but this was completely blocked by the PKA inhibitor, H89. Consequently, M-CSF grown macrophages inhibited T-cell proliferation but the inhibition ability was reduced when the COX is inhibited by indomethacin or macrophage C/EBP-β expression was decreased by siRNA transduction. Our results collectively describe the molecular basis for homeostatic macrophage differentiation by endogenous PGE2 .<br /> (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Arginase genetics
Arginase immunology
CCAAT-Enhancer-Binding Protein-beta genetics
Cell Differentiation drug effects
Cell Line
Colforsin pharmacology
Cyclic AMP Response Element-Binding Protein genetics
Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases genetics
Cyclic AMP-Dependent Protein Kinases immunology
Female
Gene Expression Regulation
Indomethacin pharmacology
Interleukin-10 genetics
Interleukin-10 immunology
Isoquinolines pharmacology
Macrophages cytology
Macrophages immunology
Membrane Glycoproteins genetics
Membrane Glycoproteins immunology
Mice
Mice, Inbred C57BL
Phenotype
Primary Cell Culture
Prostaglandin-Endoperoxide Synthases genetics
Prostaglandin-Endoperoxide Synthases immunology
Receptors, Cell Surface genetics
Receptors, Cell Surface immunology
Receptors, Immunologic
Signal Transduction
Sulfonamides pharmacology
CCAAT-Enhancer-Binding Protein-beta immunology
Cyclic AMP Response Element-Binding Protein immunology
Dinoprostone biosynthesis
Macrophage Colony-Stimulating Factor pharmacology
Macrophages drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4141
- Volume :
- 45
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 26118414
- Full Text :
- https://doi.org/10.1002/eji.201545471