Alternative activation of macrophages by prostacyclin synthase ameliorates alcohol induced liver injury.

Szczegóły
Abstrakt

Tytuł:: Alternative activation of macrophages by prostacyclin synthase ameliorates alcohol induced liver injury.
Autorzy:: Pan XY; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.; The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Wang L; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.; The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
You HM; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.; The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Cheng M; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.; The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Yang Y; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.; The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Huang C; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.; The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China.; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Li J; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China. .; The key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, 230032, China. .; Institute for Liver Diseases of Anhui Medical University, Hefei, China. .
Źródło:: Laboratory investigation; a journal of technical methods and pathology [Lab Invest] 2021 Sep; Vol. 101 (9), pp. 1210-1224. Date of Electronic Publication: 2021 Jun 10.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: 2023- : [New York] : Elsevier Inc.
Original Publication: Baltimore : Williams & Wilkins
MeSH Terms:: Cytochrome P-450 Enzyme System*/genetics
Cytochrome P-450 Enzyme System*/metabolism
Cytochrome P-450 Enzyme System*/pharmacology
Intramolecular Oxidoreductases*/genetics
Intramolecular Oxidoreductases*/metabolism
Intramolecular Oxidoreductases*/pharmacology
Macrophage Activation*/drug effects
Macrophage Activation*/genetics
Macrophages*/drug effects
Macrophages*/metabolism
Chemical and Drug Induced Liver Injury/*metabolism
Animals ; Cells, Cultured ; Ethanol/adverse effects ; Liver/drug effects ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; RAW 264.7 Cells ; Signal Transduction/drug effects
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Substance Nomenclature:: 3K9958V90M (Ethanol)
9035-51-2 (Cytochrome P-450 Enzyme System)
EC 5.3.- (Intramolecular Oxidoreductases)
EC 5.3.99.4 (prostacyclin synthetase)
Entry Date(s):: Date Created: 20210611 Date Completed: 20210827 Latest Revision: 20240229
Update Code:: 20240229
PubMed Central ID:: PMC8367821
DOI:: 10.1038/s41374-021-00531-7
PMID:: 34112940
: Czasopismo naukowe

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. Macrophages exhibit different functional states and are classified as classically activated (M1) and alternatively activated (M2) macrophages. However, the mechanisms that govern M1/M2 polarization in chronic ALD remain to be elucidated. Prostacyclin (PGI 2 ) synthase (PTGIS) is an enzyme of the prostaglandin pathway which catalyzes the conversion of Prostaglandin H 2 (PGH 2 ) to PGI 2 . PTGIS has anti-inflammatory properties. However, the function of PTGIS in ALD has not yet been determined. In this study, we demonstrated that PTGIS was downregulated in ALD and forced PTGIS expression in vivo using recombinant adeno-associated viral vector-packed PTGIS overexpression plasmid, which alleviated the inflammatory response and suppressed the macrophage M1 phenotype in mice. Loss- and gain-of function-experiments demonstrated that forced PTGIS expression inhibited the macrophage switch to the M1 phenotype and promoted M2 polarization. Furthermore, we identified the genes regulated by PTGIS through RNA-sequencing (RNA-seq) analysis. Gene ontology and KEGG pathway analyses showed that PTGIS regulates many genes involved in the immune response and is enriched in the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal transduction pathway, which plays an important role in regulating macrophage polarization. The proteins interacting with JAKs were predicted using the STRING database. The overlap between the RNA-seq and the STRING database was interleukin-6; this indicated that it was involved in macrophage polarization regulated by JAK/STAT signaling. We further explored the microRNAs that could regulate the expression of PTGIS through TargetScan. The results of luciferase assay illustrated that the expression of PTGIS was regulated by miR-140-3p.1. These results imply that PTGIS plays a pivotal role in ALD, partly by influencing macrophage polarization.
(© 2021. The Author(s).)

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